Metabotropic glutamate receptor antagonists

ABSTRACT

The present invention concerns compounds of formula. In a preferable embodiment, X represents O; R 1  represents C 1-6 alkyl; cycloC 3-12 alkyl or (cycloC 3-12 alkyl)C 1-6 alkyl, wherein one or more hydrogen atoms in a C 1-6 alkyl-moiety or in a cycloC 3-12 alkyl-moiety optionally may be replaced by C 1-6 alkyloxy, aryl, halo or thienyl; R 2  represents hydrogen; halo; C 1-6 alkyl or amino; R 3  and R 4  each independently represent hydrogen or C 1-6 alkyl; or R 2  and R 3  may be taken together to form —R 2 —R 3 —, which represents a bivalent radical of formula -Z 4 -CH 2 —CH 2 —CH 2 — or -Z 4 -CH 2 —CH 2 — with Z 4  being O or NR 11  wherein R 11  is C 1-6 alkyl; and wherein each bivalent radical is optionally substituted with C 1-6 alkyl; or R 3  and R 4  may be taken together to form a bivalent radical of formula —CH 2 —CH 2 —CH 2 —CH 2 —; R 5  represents hydrogen; Y represents O; and aryl represents phenyl optionally substituted with halo. The invention also relates to the use of a compound according to the invention as a medicament and in the manufacture of a medicament for treating or preventing glutamate-induced diseases of the central nervous system, as well as formulations comprising such a compound and processes for preparing such a compound.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 10/381,987, nowallowed, which is a National Stage application under 35 U.S.C. §371 ofPCT/EP01/11135 filed Sep. 25, 2001, which claims priority from EP00203419.7, filed Oct. 2, 2000.

The present invention is concerned with quinoline and quinolinonederivatives showing metabotropic glutamate receptor antagonisticactivity and their preparation; it further relates to compositionscomprising them, as well as their use as a medicine.

The neurotransmitter glutamate is considered to be the major excitatoryneurotransmitter in the mammalian central nervous system. The binding ofthis neurotransmitter to metabotropic glutamate receptors (mGluRs),which are a subfamily of the G-protein-coupled receptors and whichcomprise 8 distinct subtypes of mGluRs, namely mGluR1 through mGluR8,activates a variety of intracellular second messenger systems. ThemGluRs can be divided into 3 groups based on amino acid sequencehomology, the second messenger system utilized by the receptors and thepharmacological characteristics. Group I mGluRs, which comprises mGluRsubtype 1 and 5, couple to phospholipase C and their activation leads tointracellular calcium-ion mobilization. Group II mGluRs (mGluR2 and 3)and group III mGluRs (mGluR4, 6, 7 and 8) couple to adenyl cyclase andtheir activation causes a reduction in second messenger cAMP and as sucha dampening of the neuronal activity. Treatment with Group I mGluRantagonists has been shown to translate in the presynapse into a reducedrelease of neurotransmitter glutamate and to decrease theglutamate-mediated neuronal excitation via postsynaptic mechanisms.Since a variety of pathophysiological processes and disease statesaffecting the central nervous system are thought to be due to excessiveglutamate induced excitation of the central nervous system neurons,Group I mGluR antagonists could be therapeutically beneficial in thetreatment of central nervous system diseases.

WO 99/26927 discloses antagonists of Group I mGlu receptors for treatingneurological diseases and disorders, based—among others—on a quinolinestructure.

WO 99/03822 discloses bicyclic metabotropic glutamate receptor ligands,none of them based on a quinoline or quinolinone structure.

The present invention concerns compounds of formula

an N-oxide form, a pharmaceutically acceptable addition salt, aquatenary amine and a stereochemically isomeric form thereof, wherein

-   X represents O; C(R⁶)₂ with R⁶ being hydrogen, aryl or C₁₋₆alkyl    optionally substituted with amino or mono- or di(C₁₋₆alkyl)amino; S    or N—R⁷ with R⁷ being amino or hydroxy;-   R¹ represents C₁₋₆alkyl; aryl; thienyl; quinolinyl; cycloC₃₋₁₂alkyl    or (cycloC₃₋₁₂alkyl)C₁₋₆alkyl, wherein the cycloC₃₋₁₂alkyl moiety    optionally may contain a double bond and wherein one carbon atom in    the cycloC₃₋₁₂alkyl moiety may be replaced by an oxygen atom or an    NR⁸-moiety with R⁸ being hydrogen, benzyl or C₁₋₆alkyloxycarbonyl;    wherein one or more hydrogen atoms in a C₁₋₆alkyl-moiety or in a    cycloC₃₋₁₂alkyl-moiety optionally may be replaced by C₁₋₆alkyl,    hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, aminoC₁₋₆alkyl, hydroxy,    C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, halo, C₁₋₆alkyloxycarbonyl, aryl,    amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino, halo,    piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical    of formula —O—, —O—CH₂—O or —O—CH₂—CH₂—O—;    -   or a radical of formula (a-1)

-   -   -   wherein            -   Z₁ is a single covalent bond, O, NH or CH₂;            -   Z₂ is a single covalent bond, O, NH or CH₂;            -   n is an integer of 0, 1, 2 or 3;            -   and wherein each hydrogen atom in the phenyl ring                independently may optionally be replaced by halo,                hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy or hydroxyC₁₋₆alkyl;

-   or X and R¹ may be taken together with the carbon atom to which X    and R¹ are attached to form a radical of formula (b-1), (b-2) or    (b-3);

-   R² represents hydrogen; halo; cyano; C₁₋₆alkyl; C₁₋₆alkyloxy;    C₁₋₆alkylthio; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;    C₁₋₆alkylcarbonyloxyC₁₋₆alkyl; C₂₋₆alkenyl; hydroxyC₂₋₆alkenyl;    C₂₋₆alkynyl; hydroxyC₂₋₆alkynyl; tri(C₁₋₆alkyl)silaneC₂₋₆alkynyl;    amino; mono- or di(C₁₋₆alkyl)amino; mono- or    di(C₁₋₆alkyloxyC₁₋₆alkyl)amino; mono- or    di(C₁₋₆alkylthioC₁₋₆alkyl)amino; aryl; arylC₁₋₆alkyl;    arylC₂₋₆alkynyl; C₁₋₆alkyloxyC₁₋₆alkylaminoC₁₋₆alkyl; aminocarbonyl    optionally substituted with C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,    C₁₋₆alkyloxycarbonylC₁₋₆alkyl or pyridinylC₁₋₆alkyl;    -   a heterocycle selected from thienyl, furanyl, pyrrolyl,        thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl,        pyrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl,        piperidinyl and piperazinyl, optionally N-substituted with        C₁₋₆alkyloxyC₁₋₆alkyl, morpholinyl, thiomorpholinyl, dioxanyl or        dithianyl;    -   a radical —NH—C(═O)R⁹ wherein R⁹ represents        -   C₁₋₆alkyl optionally substituted with cycloC₃₋₁₂alkyl,            C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, aryl, aryloxy, thienyl,            pyridinyl, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkylthio,            benzylthio, pyridinylthio or pyrimidinylthio;        -   cycloC₃₋₁₂alkyl; cyclohexenyl; amino;            arylcycloC₃₋₁₂alkylamino; mono-or-di(C₁₋₆alkyl )amino; mono-            or di(C₁₋₆alkyloxycarbonylC₁₋₆alkyl)amino; mono- or            di(C₁₋₆alkyloxycarbonyl)amino; mono-or di(C₂₋₆alkenyl)amino;            mono- or di(arylC₁₋₆alkyl)amino; mono- or diarylamino;            arylC₂₋₆alkenyl; furanylC₂₋₆alkenyl; piperididinyl;            piperazinyl; indolyl; furyl; benzofuryl; terahydrofuryl;            indenyl; adamantyl; pyridinyl; pyrazinyl; aryl;            arylC₁₋₆alkylthio or a radical of formula (a-1);    -   a sulfonamid —NH—SO₂—R¹⁰ wherein R¹⁰ represents C₁₋₆alkyl, mono-        or poly haloC₁₋₆alkyl, arylC₁₋₆alkyl, arylC₂₋₆alkenyl, aryl,        quinolinyl, isoxazolyl or di(C₁₋₆alkyl)amino;-   R³ and R⁴ each independently represent hydrogen; halo; hydroxy;    cyano; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxyC₁₋₆alkyl;    C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; C₂₋₆alkenyl;    hydroxyC₂₋₆alkenyl; C₂₋₆alkynyl; hydroxyC₂₋₆alkynyl;    tri(C₁₋₆alkyl)silaneC₂₋₆alkynyl; amino; mono- or di(C₁₋₆alkyl)amino;    mono- or di(C₁₋₆alkyloxyC₁₋₆alkyl)amino; mono- or    di(C₁₋₆alkylthioC₁₋₆alkyl)amino; aryl; morpholinylC₁₋₆alkyl or    piperidinylC₁₋₆alkyl; or-   R² and R³ may be taken together to form —R²—R³—, which represents a    bivalent radical of formula —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,    —CH═CH—CH═CH—, -Z₄-CH═CH—, —CH═CH-Z₄-, -Z₄-CH₂—CH₂—CH₂—,    —CH₂-Z₄-CH₂—CH₂—, —CH₂—CH₂-Z₄-CH₂—, —CH₂—CH₂—CH₂-Z₄-, -Z₄-CH₂—CH₂—,    —CH₂-Z₄-CH₂— or —CH₂—CH₂-Z₄-, with Z₄ being O, S, SO₂ or NR¹¹    wherein R¹¹ is hydrogen, C₁₋₆alkyl, benzyl or C₁₋₆alkyloxycarbonyl;    and wherein each bivalent radical is optionally substituted with    C₁₋₆alkyl.-   or R³ and R⁴ may be taken together to form a bivalent radical of    formula —CH═CH—CH═CH— or —CH₂—CH₂—CH₂—CH₂—;-   R⁵ represents hydrogen; cycloC₃₋₁₂alkyl; piperidinyl; oxo-thienyl;    tetrahydrothienyl, arylC₁₋₆alkyl; C₁₋₆alkyloxyC₁₋₆alkyl;    C₁₋₆alkyloxycarbonylC₁₋₆alkyl or C₁₋₆alkyl optionally substituted    with a radical C(═O)NR_(x)R_(y), in which R_(x) and R_(y), each    independently are hydrogen, cycloC₃₋₁₂alkyl, C₂₋₆alkynyl or    C₁₋₆alkyl optionally substituted with cyano, C₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, furanyl, pyrrolidinyl, benzylthio, pyridinyl,    pyrrolyl or thienyl;-   Y represents O or S;-   or Y and R⁵ may be taken together to form ═Y—R⁵— which represents a    radical of formula    —CH═N—N═  (c-1);    —N═N—N═  (c-2); or    —N—CH═CH—  (c-3);-   aryl represents phenyl or naphthyl optionally substituted with one    or more substituents selected from halo, hydroxy, C₁₋₆alkyl,    C₁₋₆alkyloxy, phenyloxy, nitro, amino, thio, C₁₋₆alkylthio,    haloC₁₋₆alkyl, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- or    di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, cyano,    —CO—R¹², —CO—OR¹³, —NR¹³SO₂R¹², —SO₂—NR¹³R¹⁴, —NR¹³C(O)R¹²,    —C(O)NR¹³R¹⁴, —SOR¹², —SO₂R¹²; wherein each R¹², R¹³ and R¹⁴    independently represent C₁₋₆alkyl; cycloC₃₋₆alkyl; phenyl; phenyl    substituted with halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,    haloC₁₋₆alkyl, polyhaloC₁₋₆alkyl, furanyl, thienyl, pyrrolyl,    imidazolyl, thiazolyl or oxazolyl;    and when the R¹—C(═X) moiety is linked to another position than the    7 or 8 position, then said 7 and 8 position may be substituted with    R¹⁵ and R¹⁶ wherein either one or both of R¹⁵ and R¹⁶ represents    C₁₋₆alkyl, C₁₋₆alkyloxy or R¹⁵ and R¹⁶ taken together may form a    bivalent radical of formula —CH═CH—CH═CH—.

As used in the foregoing definitions and hereinafter C₁₋₆alkyl as agroup or part of a group encompasses the straight and branched chainsaturated hydrocarbon radicals having from 1 to 6 carbon atoms such as,for example, methyl, ethyl, propyl, butyl, pentyl or hexyl; C₂₋₆alkenylas a group or part of a group encompasses the straight and branchedchain hydrocarbon radicals having from 2 to 6 carbon atoms and having adouble bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl,3-methylbutenyl and the like; C₂₋₆alkynyl as a group or part of a groupdefines straight or branched chain hydrocarbon radicals having from 2 to6 carbon atoms and having a triple bond such as ethynyl, propynyl,butynyl, pentynyl, hexynyl, 3-methylbutynyl and the like; cycloC₃₋₆alkylencompasses monocyclic alkyl ring structures such as cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl; cycloC₃₋₁₂alkyl encompassesmono-, bi- or tricyclic alkyl ring structures and is generic to forexample cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norbornanyl, adamantyl.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhaloC₁₋₆alkyl as a group or part of agroup is defined as mono- or polyhalosubstituted C₁₋₆alkyl, inparticular methyl with one or more fluoro atoms, for example,difluoromethyl or trifluoromethyl. In case more than one halogen atomsare attached to an alkyl group within the definition ofpolyhaloC₁₋₆alkyl, they may be the same or different.

When any variable, e.g. aryl, occurs more than one time in anyconstituent, each definition is independent.

When any bond is drawn into a ring structure, it means that thecorresponding substituent may be linked to any atom of said ringstructure. This means for instance that the R¹—C(═X) moiety may belinked to the quinoline or quinolinone moiety in position 5, 6, 7, 8 butalso position 3 or position 4.

For therapeutic use, salts of the compounds of formula (I-A) and (I-B)are those wherein the counterion is pharmaceutically acceptable.However, salts of acids and bases which are non-pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a pharmaceutically acceptable compound. All salts,whether pharmaceutically acceptable or not are included within the ambitof the present invention.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I-A) and (I-B) are able toform. The latter can conveniently be obtained by treating the base formwith such appropriate acids as inorganic acids, for example, hydrohalicacids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid;nitric acid; phosphoric acid and the like; or organic acids, forexample, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic,2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic,ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and thelike acids. Conversely the salt form can be converted by treatment withalkali into the free base form.

The compounds of formula (I-A) and (I-B) containing acidic protons maybe converted into their therapeutically active non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts, the alkali and earth alkaline metal salts, e.g. the lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. primary, secondary and tertiary aliphatic andaromatic amines such as methylamine, ethylamine, propylamine,isopropylamine, the four butylamine isomers, dimethylamine,diethylamine, diethanolamine, dipropylamine, diisopropylamine,di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine,triethylamine, tripropylamine, quinuclidine, pyridine, quinoline andisoquinoline, the benzathine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and saltswith amino acids such as, for example, arginine, lysine and the like.Conversely the salt form can be converted by treatment with acid intothe free acid form.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I-A) and (I-B) are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I-A) and (I-B) are ableto form by reaction between a basic nitrogen of a compound of formula(I-A) or (I-B) and an appropriate quaternizing agent, such as, forexample, an optionally substituted alkylhalide, arylhalide orarylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants withgood leaving groups may also be used, such as alkyltrifluoromethanesulfonates, alkyl methanesulfonates, and alkylp-toluenesulfonates. A quaternary amine has a positively chargednitrogen. Pharmaceutically acceptable counterions include chloro, bromo,iodo, trifluoroacetate and acetate. The counterion of choice can beintroduced using ion exchange resins.

It will be appreciated that some of the compounds of formula (I-A) and(I-B) and their N-oxides, salts, quaternary amines and stereochemicallyisomeric forms may contain one or more centers of chirality and exist asstereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I-A) and (I-B), and their N-oxides, salts, quaternary amines orphysiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereoisomeric forms, said mixturescontaining all diastereomers and enantiomers of the basic molecularstructure as well as each of the individual isomeric forms of formula(I-A) and (I-B) and their N-oxides, salts, solvates or quaternary aminessubstantially free, i.e. associated with less than 10%, preferably lessthan 5%, in particular less than 2% and most preferably less than 1% ofthe other isomers. Stereochemically isomeric forms of the compounds offormula (I-A) and (I-B) are obviously intended to be embraced within thescope of the present invention. The same applies to the intermediates asdescribed herein, used to prepare end products of formula (I-A) and(I-B).

The terms cis and trans are used herein in accordance with ChemicalAbstracts nomenclature.

In some compounds of formula (I-A) and (I-B) and in the intermediatesused in their preparation, the absolute stereochemical configuration hasnot been determined. In these cases, the stereoisomeric form which wasfirst isolated is designated as “A” and the second as “B”, withoutfurther reference to the actual stereochemical configuration. However,said “A” and “B” stereoisomeric forms can be unambiguously characterizedby physicochemical characteristics such as their optical rotation incase “A” and “B” have an enantiomeric relationship. A person skilled inthe art is able to determine the absolute configuration of suchcompounds using art-known methods such as, for example, X-raydiffraction. In case “A” and “B” are stereoisomeric mixtures, they canbe further separated whereby the respective first fractions isolated aredesignated “A1” and “B1” and the second as “A2” and “B2”, withoutfurther reference to the actual stereochemical configuration.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I-A) and (I-B) wherein one or several nitrogenatoms are oxidized to the so-called N-oxide.

Some of the compounds of formula (I-A) and (I-B) may also exist in theirtautomeric form. Such forms although not explicitly indicated in theabove formula are intended to be included within the scope of thepresent invention.

Whenever used hereinafter, the term “compounds of formula (I-A) and(I-B)” is meant to also include their N-oxide forms, their salts, theirquaternary amines and their stereochemically isomeric forms. Of specialinterest are those compounds of formula (I-A) and (I-B) which arestereochemically pure.

An interesting group of compounds are those compounds of formula (I-A)and (I-B) wherein

-   X represents O; C(R⁶)₂ with R⁶ being hydrogen or aryl; or N—R⁷ with    R⁷ being amino or hydroxy;-   R¹ represents C₁₋₆alkyl, aryl; thienyl; quinolinyl; cycloC₃₋₁₂alkyl    or (cycloC₃₋₁₂alkyl)C₁₋₆alkyl, wherein the cycloC₃₋₁₂alkyl moiety    optionally may contain a double bond and wherein one carbon atom in    the cycloC₃₋₁₂alkyl moiety may be replaced by an oxygen atom or an    NR⁸-moiety with R⁸ being benzyl or C₁₋₆alkyloxycarbonyl; wherein one    or more hydrogen atoms in a C₁₋₆alkyl-moiety or in a    cycloC₃₋₁₂alkyl-moiety optionally may be replaced by C₁₋₆alkyl,    haloC₁₋₆alkyl, hydroxy, C₁₋₆allyloxy, arylC₁₋₆alkyloxy, halo, aryl,    mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino, halo,    piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical    of formula —O— or —O—CH₂—CH₂—O—;    -   or a radical of formula (a-1)

-   -   -   wherein            -   Z₁ is a single covalent bond, O or CH₂;            -   Z₂ is a single covalent bond, O or CH₂;            -   n is an integer of 0, 1, or 2;            -   and wherein each hydrogen atom in the phenyl ring                independently may optionally be replaced by halo or                hydroxy;

    -   or X and R¹ may be taken together with the carbon atom to which        X and R¹ are attached to form a radical of formula (b-1), (b-2)        or (b-3);

-   R² represents hydrogen; halo; cyano; C₁₋₆alkyl; C₁₋₆alkyloxy;    C₁₋₆alkylthio; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; C₂₋₆alkenyl;    hydroxyC₂₋₆alkenyl; C₂₋₆alkynyl; hydroxyC₂₋₆alkynyl;    tri(C₁₋₆alkyl)silaneC₂₋₆alkynyl; amino; mono- or di(C₁₋₆alkyl)amino;    mono- or di(C₁₋₆alkyloxyC₁₋₆alkyl)amino; mono- or    di(C₁₋₆alkylthioC₁₋₆alkyl)amino; aryl; arylC₁₋₆alkyl;    arylC₂₋₆alkynyl; C₁₋₆alkyloxyC₁₋₆alkylaminoC₁₋₆alkyl; aminocarbonyl    optionally substituted with C₁₋₆alkyloxycarbonylC₁₋₆alkyl; a    heterocycle selected from thienyl, furanyl, thiazolyl and    piperidinyl, optionally N-substituted with morpholinyl or    thiomorpholinyl; a radical —NH—C(═O)R⁹ wherein R⁹ represents    C₁₋₆alkyl optionally substituted with cycloC₃₋₁₂alkyl, C₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, aryl, aryloxy, thienyl, pyridinyl, mono- or    di(C₁₋₆alkyl)amino, C₁₋₆alkylthio, benzylthio, pyridinylthio or    pyrimidinylthio; cycloC₃₋₁₂alkyl; cyclohexenyl; amino;    arylcycloC₃₋₁₂alkylamino; mono-or-di(C₁₋₆alkyl)amino; mono- or    di(C₁₋₆alkyloxycarbonylC₁₋₆alkyl)amino; mono- or    di(C₁₋₆alkyloxycarbonyl)amino; mono-or di(C₂₋₆alkenyl)amino; mono-    or di(arylC₁₋₆alkyl)amino; mono- or diarylamino; arylC₂₋₆alkenyl;    furanylC₂₋₆alkenyl; piperididinyl; piperazinyl; indolyl; furyl;    benzofuryl; tetrahydrofuryl; indenyl; adamantyl; pyridinyl;    pyrazinyl; aryl or a radical of formula (a-1); a sulfonamid    —NH—SO₂—R¹⁰ wherein R¹⁰ represents C₁₋₆alkyl, mono- or poly    haloC₁₋₆alkyl, arylC₆alkyl or aryl;-   R³ and R⁴ each independently represent hydrogen; C₁₋₆alkyl;    C₁₋₆alkyloxyC₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; or-   R²and R³ may be taken together to form —R²—R³—, which represents a    bivalent radical of formula —(CH₂)₄—, —(CH₂)₅—, -Z₄-CH═CH—,    -Z₄-CH₂—CH₂—CH₂— or -Z₄-CH₂—CH₂—, with Z₄ being O, S, SO₂ or NR¹¹    wherein R¹¹ is hydrogen, C₁₋₆alkyl, benzyl or C₁₋₆alkyloxycarbonyl;    and wherein each bivalent radical is optionally substituted with    C₁₋₆alkyl;-   or R³ and R⁴ may be taken together to form a bivalent radical of    formula —CH═CH—CH═CH— or —CH₂—CH₂—CH₂—CH₂—;-   R⁵ represents hydrogen; piperidinyl; oxo-thienyl; tetrahydrothienyl,    arylC₁₋₆alkyl; C₁₋₆alkyloxycarbonylC₁₋₆alkyl or C₁₋₆alkyl optionally    substituted with a radical C(═O)NR_(x)R_(y), in which R_(x) and    R_(y), each independently are hydrogen, cycloC₃₋₁₂alkyl, C₂₋₆alkynyl    or C₁₋₆alkyl optionally substituted with cyano, C₁₋₆alkyloxy or    C₁₋₆alkyloxycarbonyl;-   Y represents O or S;-   or Y and R⁵ may be taken together to form ═Y—R⁵— which represents a    radical of formula    —CH═N—N═  (c-1); or    —N═N—N═  (c-2);-   aryl represents phenyl or naphthyl optionally substituted with one    or more substituents selected from halo, C₁₋₆alkyloxy, phenyloxy,    mono-or di(C₁₋₆alkyl)amino and cyano;    and when the R¹—C(═X) moiety is linked to another position than the    7 or 8 position, then said 7 and 8 position may be substituted with    R¹⁵ and R¹⁶ wherein either one or both of R¹⁵ and R¹⁶ represents    C₁₋₆alkyl or R¹⁵ and R¹⁶ taken together may form a bivalent radical    of formula —CH═CH—CH═CH—.

A further most interesting group of compounds comprises those compoundsof formula (I-A) and (I-B) wherein X represents O;

-   R¹ represents C₁₋₆alkyl; cycloC₃₋₁₂alkyl or    (cycloC₃₋₁₂alkyl)C₁₋₆alkyl, wherein one or more hydrogen atoms in a    C₁₋₆alkyl-moiety or in a cycloC₃₋₁₂alkyl-moiety optionally may be    replaced by C₁₋₆alkyloxy, aryl, halo or thienyl;-   R² represents hydrogen; halo; C₁₋₆alkyl or amino;-   R³ and R⁴ each independently represent hydrogen or C₁₋₆alkyl; or-   R² and R³ may be taken together to form —R²—R³—, which represents a    bivalent radical of formula -Z₄-CH₂—CH₂—CH₂— or -Z₄-CH₂—CH₂— with Z₄    being O or NR¹¹ wherein R¹¹ is C₁₋₆alkyl; and wherein each bivalent    radical is optionally substituted with C₁₋₆alkyl;    -   or R³ and R⁴ may be taken together to form a bivalent radical of        formula —CH₂—CH₂—CH₂—CH₂—;-   R⁵ represents hydrogen;-   Y represents O; and-   aryl represents phenyl optionally substituted with halo.

A further interesting group of compounds comprises those compounds offormula (I-A) and (I-B) wherein the R¹—C(═X) moiety is linked to thequinoline or quinolinone moiety in position 6.

In order to simplify the structural representation of some of thepresent compounds and intermediates in the following preparationprocedures, the quinoline or the quinolinone moiety will hereinafter berepresented by the symbol Q.

The compounds of formula (I-A) or (I-B), wherein X represents O, saidcompounds being represented by formula (I_(A/B)-a), can be prepared byoxidizing an intermediate of formula (II) in the presence of a suitableoxidizing agent, such as potassium permanganate, and a suitablephase-transfer catalyst, such as tris(dioxa-3,6-heptyl)amine, in asuitable reaction-inert solvent, such as for example dichloromethane.

Compounds of formula (I_(A/B)-a) may also be prepared by reacting anintermediate of formula (III) with an intermediate of formula (IV),wherein W₁ represents a halo atom, e.g. bromo, in the presence of butyllithium and a suitable reaction-inert solvent, such as for exampletetrahydrofuran.

Alternatively, compounds of formula (I_(A/B)-a) may also be prepared byreacting an intermediate of formula (V) with an intermediate of formula(IV) in the presence of butyl lithium and a suitable reaction-inertsolvent, such as for example tetrahydrofuran.

Compounds of formula (I_(A/B)-a), wherein the R¹ substituent is linkedto the carbonyl moiety via an oxygen atom, said R¹ substituent beingrepresented by O—R^(1a) and said compounds by formula (I_(A/B)-a-1), canbe prepared by reacting an intermediate of formula (VI) with anintermediate of formula (VII) in the presence of a suitable acid, suchas sulfuric acid.

Compounds of formula (I-A), wherein R² represents methylcarbonyl, saidcompounds being represented by formula (I-A-1), can be prepared byreacting an intermediate of formula (VIII) in the presence of a suitableacid, such as hydrochloric acid, and a suitable reaction-inert solvent,such as for example tetrahydrofuran.

The compounds of formula (I) may also be converted into each otherfollowing art-known transformations.

Compounds of formula (I-A) wherein R² is a halo atom, such as chloro,can be converted into a compound of formula (I-A), wherein R² is anotherhalo atom, such as fluoro or iodo, by reaction with a suitablehalogenating agent, such as for example potassium fluoride or sodiumiodide, in the presence of a suitable reaction-inert solvent, e.g.dimethyl sulfoxide or acetonitrile and optionally in the presence ofacetyl chloride.

Compounds of formula (I-A), wherein R² is a suitable leaving group, suchas a halo atom, e.g. chloro, iodo, said leaving group being representedby W² and said compounds by (I-A-2), can be converted into a compound offormula (I-A) wherein R² is cyano, said compound being represented byformula (I-A-3), by reaction with a suitable cyano-introducing agent,such as for example trimethylsilanecarbonitrile, in the presence of asuitable base such as N,N-diethylethanamine and a suitable catalyst,such as for example tetrakis(triphenylphosphine)palladium.

Compounds of formula (I-A-2) can also be converted into a compound offormula (I-A-4) by reaction with C₂₋₆alkynyltri(C₁₋₆alkyl)silane in thepresence of CuI, an appropriate base, such as for exampleN,N-ethylethanamine, and an appropriate catalyst, such as for exampletetrakis(triphenylphosphine)palladium. Compounds of formula (I-A-4) canon their turn be converted into a compound of formula (I-A-5) byreaction with potassium fluoride in the presence of a suitable acid suchas acetic acid, or by reaction with a suitable base, such as potassiumhydroxide, in the presence of a suitable reaction-inert solvent, such asan alcohol, e.g. methanol and the like.

Compounds of formula (I-A-2) can also be converted into a compound offormula (I-A-6) by reaction with an intermediate of formula (IX) in thepresence of CuI, a suitable base, such as for exampleN,N-diethylethanamine, and a suitable catalyst such astetrakis(triphenylphosphine)palladium.

Compounds of formula (I-A-2) can also be converted into a compoundwherein R² is C₁₋₆alkyl, said compound being represented by formula(I-A-8) in the presence of a suitable alkylating agent, such as forexample Sn(C₁₋₆alkyl)₄, or into a compound wherein R² is C₂₋₆alkenyl,said compound being represented by formula (I-A-9) in the presence of asuitable alkenylating agent, such as for exampleSn(C₂₋₆alkenyl)(C₁₋₆alkyl)₃, both reactions in the presence of asuitable catalyst, such as for exampletetrakis(triphenylphosphine)palladium and a reaction-inert solvent, suchas for example toluene or dioxane.

Compounds of formula (I-A-2) can also be converted into a compound offormula (I-A-7) wherein Z represents O or S, by reaction with anintermediate of formula (X) optionally in the presence of a suitablebase such as dipotassium carbonate and a reaction-inert solvent, such asN,N-dimethyl formamide.

Compounds of formula (I-A-2) can also be converted into a compound offormula (I-A), wherein R² is C₁₋₆alkyloxycarbonyl, said compound beingrepresented by formula (I-A-10) and a compound of formula (I-A), whereinR² is hydrogen, said compound being represented by formula (I-A-11), byreaction with a suitable alcohol of formula

C₁₋₆alkylOH and CO in the presence of a suitable catalyst, such as forexample palladium(II)acetate, triphenylphosphine, a suitable base suchas dipotassium carbonate and a reaction-inert solvent, such asN,N-dimethylformamide.

Compounds of formula (I-A-11) can also be prepared by reacting acompound of formula (I-A-2) with Zn in the presence of a suitable acidsuch as acetic acid.

Compounds of formula (I-A-2) can also be converted into a compound offormula (I-A), wherein R² is aminocarbonyl substituted withC₁₋₆alkyloxycarbonylC₁₋₆alkyl, said compound being represented byformula (I-A-12), by reaction with an intermediate of formulaH₂N—C₁₋₆alkyl-C(═O)—O—C₁₋₆alkyl in the presence of CO, a suitablecatalyst such as tetrakis(triphenylphosphine)palladium, a suitable base,such as for example N,N-diethylethanamine, and a suitable reaction-inertsolvent, such as for example toluene.

Compounds of formula (I-A-2) can also be converted into a compound offormula (I-A) wherein R² is aryl or a heterocycle selected from thegroup described in the definition of R² hereinabove, said R² beingrepresented by R^(2a) and said compound by formula (I-A-13) by reactionwith an intermediate of formula (XI), (XII) or (XIII) in the presence ofa suitable catalyst such as for exampletetrakis(triphenylphosphine)palladium and a suitable reaction-inertsolvent, such as for example dioxane.

Compounds of formula (I-A-2) can also be converted into a compound offormula (I-B), wherein Y and R⁵ are taken together to form a radical offormula (b-1) or (b-2), said compound being represented by formula(I-B-1) or (I-B-2), by reaction with hydrazincarboxaldehyde or sodiumazide in a suitable reaction-inert solvent, such as an alcohol, e.g.butanol, or N,N-diethylformamide.

Compounds of formula (I-A-11) can be converted into the correspondingN-oxide, represented by formula (I-A-14), by reaction with a suitableperoxide, such as 3-chloro-benzenecarboperoxoic acid, in a suitablereaction-inert solvent, such as for example methylene chloride. Saidcompound of formula (I-A-14) can further be converted into a compound offormula (I-B), wherein R⁵ is hydrogen, said compound being representedby formula (I-B-3), by reaction with 4-methyl-benzene sulfonyl chloridein the presence of a suitable base, such as for example dipotassiumcarbonate and a suitable reaction-inert solvent, such as for examplemethylene chloride.

Compounds of formula (I-B-3) can also be prepared from a compound offormula (I-A), wherein R² is C₁₋₆alkyloxy, said compound beingrepresented by formula (I-A-15), by reaction with a suitable acid, suchas hydrochloric acid, in the presence of a suitable reaction-inertsolvent, such as for example tetrahydrofuran.

Compounds of formula (I-B-3) can be converted into a compound of formula(I-B), wherein R⁵ represents C₁₋₆alkyl, said compound being representedby formula (I-B-4), by reaction with an appropriate alkylating agent,such as for example an intermediate of formula (XIV), wherein W₃represents a suitable leaving group such as a halo atom e.g. iodo, inthe presence of potassium tert. butoxide and in the presence of asuitable reaction-inert solvent, such as for example tetrahydrofuran.

Compounds of formula (I-B-3) can also be converted into a compound offormula (I-B), wherein R⁵ is C₁₋₆alkyloxycarbonylC₁₋₆alkyl orarylC₁₋₆alkyl, said R⁵ being represented by R^(5a) and said compoundbeing represented by formula (I-B-5), by reaction with an intermediateof formula (XV), wherein W₄ represents a suitable leaving group, such asa halo atom, e.g. bromo, chloro and the like, in the presence of asuitable base, such as for example sodium hydride and a suitablereaction-inert solvent, such as for example N,N-dimethylformamide.

Compounds of formula (I-A-2) can also be converted into a compound offormula (I-B), wherein R⁵ is hydrogen and Y is S, said compound beingrepresented by formula (I-B-6), by reaction with H₂N—C(═S)—NH₂ in thepresence of a suitable base, such as potassium hydroxide, and a suitablereaction-inert solvent, such as an alcohol, for example ethanol, orwater. Compounds of formula (I-B-6) can further be converted into acompound of formula (I-A), wherein R² is C₁₋₆alkylthio, said compoundbeing represented by formula (I-A-16), by reaction with a suitableC₁₋₆alkylhalide, such as for example C₁₋₆alkyliodide, in the presence ofa suitable base, such as dipotassium carbonate, and a suitable solvent,such as for example acetone.

Compounds of formula (I_(A/B)-a) can be converted into a compounds offormula (I-A) or (I-B), wherein X is N—R⁷, said compound beingrepresented by formula (I_(A/B)-b), by reaction with an intermediate offormula (XVI), optionally in the presence of a suitable base, such asfor example N,N-diethylethanamine, and in the presence of a suitablereaction-inert solvent, such as an alcohol, e.g. ethanol.

As already indicated in the preparation procedure of compounds offormula (I-A-13) described above, the compounds of formula (I) may alsobe converted to the corresponding N-oxide forms following art-knownprocedures for converting a trivalent nitrogen into its N-oxide form.Said N-oxidation reaction may generally be carried out by reacting thestarting material of formula (I) with an appropriate organic orinorganic peroxide. Appropriate inorganic peroxides comprise, forexample, hydrogen peroxide, alkali metal or earth alkaline metalperoxides, e.g. sodium peroxide, potassium peroxide; appropriate organicperoxides may comprise peroxy acids such as, for example,benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid,e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, allylhydroperoxides, e.g. tert-butyl hydroperoxide.Suitable solvents are, for example, water, lower alkanols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

Some of the intermediates and starting materials used in the abovereaction procedures are commercially available, or may be synthesizedaccording to procedures already described in the literature.

Intermediates of formula (II) may be prepared by reacting anintermediate of formula (XVII) with an intermediate of formula (XVIII),wherein W₅ represents a suitable leaving group such as a halo atom, e.g.chloro, bromo and the like, in the presence of magnesium, diethyletherand a suitable reaction-inert solvent, such as diethylether.

Intermediates of formula (XVII) may be prepared by oxidizing anintermediate of formula (XIX) in the presence of a suitable oxidizingagent, such as MnO₂, and a suitable reaction-inert solvent, such asmethylene chloride.

Intermediates of formula (XIX) can be prepared by reducing anintermediate of formula (XX) in the presence of a suitable reducingagent such as lithium aluminium hydride, and a suitable reaction-inertsolvent, such as tetrahydrofuran.

Intermediates of formula (XX), wherein Q represents a quinoline moietyoptionally substituted in position 3 with C₁₋₆alkyl and wherein thecarbonyl moiety is placed in position 6, said intermediates beingrepresented by formula (XX-a), can be prepared by reacting anintermediate of formula (XXI) with an intermediate of formula (XXII) inthe presence of sodium 3-nitro-benzene sulfonate, a suitable acid, suchas sulfuric acid, and a suitable alcohol, e.g. methanol, ethanol,propanol, butanol and the like.

Alternatively, intermediates of formula (II) can also be prepared byreacting an intermediate of formula (XXIII) with an intermediate offormula (XXIV), wherein W₆ is a suitable leaving group, such as a haloatom, e.g. bromo, chloro and the like, in the presence of a suitableagent, such as butyl lithium and a suitable reaction-inert solvent, suchas tetrahydrofuran.

Intermediates of formula (XXIII) can be prepared by oxidizing anintermediate of formula (XXV) using the Moffatt Pfitzner or Swernoxidation (dimethylsulfoxide adducts with dehydrating agents e.g. DCC,Ac₂O, SO₃, P₄O₁₀, COCl₂ or Cl—CO—COCl) in an inert solvent such asmethylene chloride.

Intermediates of formula (XXV) can be prepared by reducing anintermediate of formula (XXVI) in the presence of a suitable reducingagent, such as for example lithium aluminium hydride and a suitablereaction-inert solvent, such as benzene.

Intermediates of formula (XXVI) can be prepared from an intermediate offormula (XXVII) by esterification in the presence of a suitable alcohol,such as methanol, ethanol, propanol, butanol and he like, and a suitableacid, such as sulfuric acid.

Intermediates of formula (XXVII), wherein R¹ represents a radical offormula (a-1) with Z₁ being O, Z₂ being CH₂ and n being 1, saidintermediates being represented by formula (XXVII-a), can be prepared byreducing an intermediate of formula (XXVIII) in the presence of asuitable reducing agent such as hydrogen, and a suitable catalyst, suchas palladium on charcoal, and a suitable acid such as acetic acid. WhenR¹ of intermediate (XXVII) represents an optionally substituted phenylmoiety, it can also be converted into an optionally substitutedcyclohexyl moiety by reduction in the presence of a suitable reducingagent such as rhodium on Al₂O₃, and a suitable reaction-inert solvent,such as tetrahydrofuran.

Intermediates of formula (IV), wherein Q represents a quinoline moietysubstituted in position 2 with halo,e.g. chloro, said intermediatesbeing represented by formula (IV-a), can be prepared by reacting anintermediate of formula (IV), wherein Q represents a quinolinone moietywith R⁵ being hydrogen, said intermediate being represented by formula(IV-b), in the presence of POCl₃.

Intermediates of formula (IV-a), wherein R⁴ is hydrogen, saidintermediates being represented by formula (IV-a-1), can also beprepared by reacting an intermediate of formula (XXIX) with POCl₃ in thepresence of N,N-diethylformamide (Vilsmeier-Haack formylation followedby cyclization).

Intermediates of formula (XXIX) may be prepared by reacting anintermediate of formula (XXX) with an intermediate of formula (XXXI),wherein W₇ represents a suitable leaving group, such as a halo atom,e.g. chloro, in the presence of a suitable base, such as for exampleN,N-diethylethanamine, and a suitable reaction-inert solvent, such asmethylene chloride.

Intermediates of formula (IV-a) can be converted into an intermediate offormula (IV-c) by reaction with an intermediate of formula (XXXII) inthe presence of a suitable reaction-inert solvent, such as an alcohol,e.g. methanol and the like.

Intermediates of formula (IV-a) can also be converted into anintermediate of formula (IV-d-1) by reaction with a suitable amine offormula (XXXIII-a), wherein Z₃ and Z₄ each independently representhydrogen, C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkylthioC₁₋₆alkyl orinto an intermediate of formula (IV-d-2) by reaction with a suitableamine of formula (XXXIII-b), wherein Z₃ and Z₄ are taken together toform a heterocycle as defined hereinabove in the definition of R²provided that the heterocycle comprises at least one nitrogen atom, inthe presence of a suitable base, such as for example dipotassiumcarbonate, and a reaction-inert solvent, such as N,N-dimethylformamide.

Intermediates of formula (IV-a), wherein R³ represents CH₂—CH₂—CH₂—Cl,said intermediates being represented by formula (IV-a-2), can also beconverted into an intermediate of formula (IV), wherein R² and R³ aretaken together to form a bivalent radical of formula —O—CH₂—CH₂—CH₂—,said intermediate being represented by formula (IV-e-1), by reactionwith a suitable acid, such as hydrochloric acid and the like.Intermediates of formula (IV-a-2) can also be converted into anintermediate of formula (IV), wherein R² and R³ are taken together toform a bivalent radical of formula —S—CH₂—CH₂—CH₂—, said intermediatebeing represented by formula (IV-e-2), by reaction with H₂N—C(═S)—NH₂ inthe presence of a suitable reaction-inert solvent, such as an alcohol,e.g. ethanol.

Intermediates of formula (V) may be prepared by reacting an intermediateof formula (XXVII) with an intermediate of formula CH₃—NH—O—CH₃ in thepresence of 1,1′-carbonyldiimidazole and a suitable reaction-inertsolvent, such as methylene chloride.

Intermediates of formula (VII), wherein Q represents a quinoline moiety,in particular a quinoline moiety wherein R² is ethyl, R³ is methyl andR⁴ is hydrogen, and the carboxyl moiety is placed in position 6, saidintermediates being represented by formula (VII-a), can be prepared byreaction an intermediate of formula (XXXIV) in the presence of asuitable aldehyde, such as CH₃—CH₂—CH(═O), (CH₂O)_(n), ZnCl₂, FeCl₃ anda suitable reaction-inert solvent, such as an alcohol, for exampleethanol.

Intermediates of formula (VIII) can be prepared by reacting anintermediate of formula (XXXV) with an intermediate of formula (XXXVI)in the presence of a suitable catalyst, such as for exampletetrakis(triphenylphosphine)palladium and a suitable reaction-inertsolvent, such as for example dioxane.

Still some other preparations can be devised, some of them are disclosedfurther in this application with the Examples.

Pure stereoisomeric forms of the compounds and the intermediates of thisinvention may be obtained by the application of art-known procedures.Diastereomers may be separated by physical separation methods such asselective crystallization and chromatographic techniques, e.g. liquidchromatography using chiral stationary phases. Enantiomers may beseparated from each other by the selective crystallization of theirdiastereomeric salts with optically active acids. Alternatively,enantiomers may be separated by chromato-graphic techniques using chiralstationary phases. Said pure stereoisomeric forms may also be derivedfrom the corresponding pure stereoisomeric forms of the appropriatestarting materials, provided that the reaction occurs stereo-selectivelyor stereospecifically. Preferably, if a specific stereoisomer isdesired, said compound will be synthesized by stereoselective orstereospecific methods of preparation. These methods will advantageouslyemploy chirally pure starting materials. Stereoisomeric forms of thecompounds of formula (I) are obviously intended to be included withinthe scope of the invention.

A stereoisomer of a compound of formula (I-A) or (I-B) such as a cisform, may be converted into another stereoisomer such as thecorresponding trans form by reacting the compound with a suitable acid,such as hydrochloric acid, in the presence of a suitable reaction-inertsolvent, such as for example tetrahydrofuran.

The compounds of formula (I-A) and (I-B), the N-oxides, thepharmaceutically acceptable addition salts, the quaternary amines andthe stereochemically isomeric forms thereof show mGluR antagonisticactivity, more in particular Group I mGluR antagonistic activity. TheGroup I mGluR specifically antagonized by the present compounds is themGluR1.

The mGluR1 antagonistic activity of the present compounds can bedemonstrated in the Signal transduction on cloned rat mGluR1 in CHOcells test and the Cold allodynia test in rats with a Bennett ligation,as described hereinafter.

Due to their mGluR antagonistic activity, more in particular their GroupI mGluR antagonistic activity and even more in particular, their mGluR1antagonistic activity, the compounds of formula (I-A) or (I-B), theirN-oxides, pharmaceutically acceptable addition salts, quaternary aminesand stereochemically isomeric forms are useful in the treatment orprevention of glutamate-induced diseases of the central nervous system.Diseases in which a role for glutamate has been demonstrated includedrug addiction or abstinence (dependence, opioid tolerance, opioidwithdrawal), hypoxic, anoxic and ischemic injuries (ischemic stroke,cardiac arrest), pain (neuropathic pain, inflammatory pain,hyperalgesia), hypoglycemia, diseases related to neuronal damage, braintrauma, head trauma, spinal cord injury, myelopathy, dementia, anxiety,schizophrenia, depression, impaired cognition, amnesia, bipolardisorders, conduct disorders, Alzheimer's disease, vascular dementia,mixed (Alzheimer's and vascular) dementia, Lewy Body disease, deliriumor confusion, Parkinson's disease, Huntington's disease, Down syndrome,epilepsy, aging, Amyotrophic Lateral Sclerosis, multiple sclerosis, AIDS(Acquired Immune Deficiency Syndrome) and AIDS related complex (ARC).

In view of the utility of the compounds of formula (I-A) and (I-B),there is provided a method of treating warm-blooded animals, includinghumans, suffering from glutamate-induced diseases of the central nervoussystem. Said method comprises the administration, preferably oraladministration, of an effective amount of a compound of formula (I-A) or(I-B), a N-oxide form, a pharmaceutically acceptable addition salt, aquaternary amine or a possible stereoisomeric form thereof, towarm-blooded animals, including humans.

In view of the above described pharmacological properties, the compoundsof formula (I-A) and (I-B) or any subgroup thereof, their N-oxides,pharmaceutically acceptable addition salts, quaternary amines andstereochemically isomeric forms, may be used as a medicine. Inparticular, the use of a compound of formula (I-A) and (I-B) in themanufacture of a medicament for treating or preventing glutamate-induceddiseases of the central nervous system is provided. More in particular,the present compounds may be used as neuroprotectants, analgesics oranticonvulstants.

The present invention also provides compositions for treating orpreventing glutamate-induced diseases of the central nervous systemcomprising a therapeutically effective amount of a compound of formula(I-A) or (I-B) and a pharmaceutically acceptable carrier or diluent.

Therefore, the compounds of the present invention or any subgroupthereof may be formulated into various pharmaceutical forms foradministration purposes. As appropriate compositions there may be citedall compositions usually employed for systemically administering drugs.To prepare the pharmaceutical compositions of this invention, atherapeutically effective amount of a particular compound, in base oraddition salt form, as the active ingredient is combined in intimateadmixture with a pharmaceutically acceptable carrier, which carrier maytake a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirably in unitary dosage form suitable, preferably, foradministration orally, rectally, topically, percutaneously or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed, suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, emulsions,elixirs and solutions: or solid carriers such as starches, sugars,kaolin, lubricants, binders, disintegrating agents and the like in thecase of powders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. Asappropriate compositions for topical application there may be cited allcompositions usually employed for topically administering drugs e.g.creams, gel, dressings, shampoos, tinctures, pastes, ointments, salves,powders and the like. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such unit dosage forms are tablets (includingscored or coated tablets), capsules, pills, suppositories, powderpackets, wafers, injectable solutions or suspensions, teaspoonfuls,tablespoonfuls and the like, and segregated multiples thereof.

The therapeutically effective dose or frequency of administrationdepends on the particular compound of formula (I-A) or (I-B) used, theparticular condition being treated, the severity of the condition beingtreated the age, weight, sex, fed or fasted state, and the generalphysical condition of the particular patient as well as other medicationthe individual may be taking, as is well known to those skilled in theart. Furthermore, it is evident that said therapeutically effective doseor the effective daily dose may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. It maybe appropriate to administer the required dose as two, three, four ormore sub-doses at appropriate intervals throughout the day. Saidsub-doses may be formulated as unit dosage forms.

The following examples are intended to illustrate the present invention.

EXPERIMENTAL PART

Hereinafter, “DMF” is defined as N,N-dimethylformamide, “DIPE” isdefined as diisopropylether, “DMSO” is defined as dimethylsulfoxide,“BHT” is defined as 2,6-bis(1,1-dimethylethyl)-4-methylphenol, and “THF”is defined as tetrahydrofuran.

Preparation of the Intermediates

EXAMPLE A1

Preparation of

A mixture of 4-(1-methylethoxy)benzoic acid (0.083 mol) and Rh/Al₂O₃ 5%(10 g) in THF (220 ml) was hydrogenated at 50° C. (under 3 bar pressureof H₂) for 1 night. The mixture was filtered over celite, washed withTHF and evaporated. Yield: 16 g of intermediate 1 (100%).

EXAMPLE A2

Preparation of 2-ethyl-3-methyl-6-quinolinecarboxylic acid (interm. 2)

A mixture of 4-aminobenzoic acid (0.299 mol) in ethanol (250 ml) wasstirred at room temperature. ZnCl₂ (0.0367 mol) and (CH₂O)_(n) (10 g)were added. FeCl₃.6H₂O (0.5 mol) was added portionwise and thetemperature rised till 60-65° C. Propanal (30 ml) was added dropwiseover a 2 hours period. The mixture was refluxed for 2 hours and kept atroom temperature for 12 hours. The mixture was poured into water andfiltered through celite. The filtrate was acidified till pH=7 with HCl6N and the mixture was evaporated till dryness. The residue was usedwithout further purification. Yield: 56.1 g of2-ethyl-3-methyl-6-quinolinecarboxylic acid (interm. 2).

EXAMPLE A3

Preparation of

Pentanoyl chloride (0.2784 mol) was added at 5° C. to a mixture of4-bromobenzenamine (0.232 mol) and N,N-ethylethanamine (0.2784 mol) inCH₂Cl₂ (400 ml). The mixture was stirred at room temperature overnight,poured out into water and extracted with CH₂Cl₂. The organic layer wasseparated, washed with a concentrated NH₄OH solution and water, dried(MgSO₄), filtered and the solvent was evaporated. The residue (60 g) wascrystallized from diethylether. The precipitate was filtered off anddried. The residue (35 g, 63%) was taken up in CH₂Cl₂. The organic layerwas separated, washed with a 10% K₂CO₃ solution, washed with water,dried (MgSO₄), filtered and the solvent was evaporate Yield: 30 g ofintermediate (3) (54%).

EXAMPLE A4

Preparation of

A mixture of 6-bromo-2(1H)-quinolinone (0.089 mol) in POCl₃ (55 ml) wasstirred at 60° C. overnight, then at 100° C. for 3 hours and the solventwas evaporated. The residue was taken up in CH₂Cl₂, poured out into icewater, basified with NH₄OH conc., filtered over celite and extractedwith CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filteredand the solvent was evaporated. Yield. 14.5 g of intermediate (4) (67%).

EXAMPLE A5

a) Preparation of

DMF (37 ml) was added dropwise at 10° C. under N₂ flow to POCl₃ (108ml). After complete addition, the mixture was allowed to warm to roomtemperature. N-(4-bromophenyl)butanamide (0.33 mol) was addedportionwise. The mixture was stirred at 85° C. overnight, then allowedto cool to room temperature and poured out on ice (exothermic reaction).The precipitate was filtered off, washed with a small amount of waterand dried (vacuum). The residue was washed with EtOAc/diethyl ether anddried. Yield: 44.2 g of intermediate (5) (50%).

b) Preparation of

A mixture of intermediate (5) (0.162 mol) in methanol (600 ml), and asolution of methanol sodium salt in methanol at 35% (154 ml) was stirredand refluxed overnight. The mixture was poured out on ice. Theprecipitate was filtered off, washed with a small amount of water andtaken up in CH₂Cl₂, K₂CO₃ 10% was added and the mixture was extractedwith CH₂Cl₂. The organic layer was separated, washed with water, dried(MgSO₄), filtered and the solvent was evaporated. Yield: 31.9 g ofintermediate (6) (74%).

EXAMPLE A6

Preparation of

1,1′-Carbonylbis-1H-imidazole (0.074 mol) was added portionwise to amixture of 4-methoxycyclohexanecarboxylic acid (0.063 mol) in CH₂Cl₂(200 ml). The mixture was stirred at room temperature for 1 hour. ThenN-methoxymethanamine (0.074 mol) was added. The mixture was stirred atroom temperature overnight, poured out into H₂O and extracted withCH₂Cl₂. The organic layer was separated, washed several times with H₂O,drized (MgSO₄), filtered and the solvent was evaporated. Yield: 12.6 gof interm. 7.

EXAMPLE A7

a) A mixture of 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (0.30mol) in acetic acid (400 ml) was hydrogenated with Pd/C (3 g) as acatalyst. After uptake of H₂ (3 equiv), the catalyst was filtered off.The filtrate was evaporated. The residue was stirred in petroleum ether.The precipitate was filtered off and dried (vacuum; 70° C.). Afterrecrystallization from CHCl₃/CH₃OH, the precipitate was filtered off anddried (vacuum; 80° C. and high vacuum; 85° C.). Yield: 8.8 g of6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (interm. 8)(15.0%).

b) A mixture of intermediate (8) (0.255 mol) in ethanol (400 ml) andH₂SO₄ (5 ml) was stirred and refluxed for 8 hours. The solvent wasevaporated till dryness. The residue was dissolved in CH₂Cl₂. Theorganic layer was separated, washed with K₂CO₃ 10%, dried (MgSO₄),filtered and the solvent was evaporated. Yield: 45 g of ethyl6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (interm. 9) (79%).

c) Reaction under N₂. A mixture of sodiumbis(2-methoxyethoxy)aluminumhydride, 70 wt % solution in methylbenzene3.4 M (0.44 mol) in benzene (150 ml) (reflux) was added dropwise during1 hour to a refluxed mixture of interm. 9 (0.22 mol) and benzene (600ml). After stirring for 2.5 hours at reflux temperature, the mixture wascooled to ±15° C. The mixture was decomposed by adding dropwise ethanol(30 ml) and water (10 ml). This mixture was poured out onto ice/waterand this mixture was acidified with concentrated hydrochloric acid. Thismixture was extracted with diethyl ether (500 ml). The separated organiclayer was washed with water, dried, filtered and the solvent wasevaporated. The residue was purified by column chromotoghaphy oversilica gel (eluent: CHCl₃). The desired fraction was collected and theeluent was evaporated. Yield. 34 g of6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol (interm. 10) (85%).

d) Reaction under N₂. To a stirred and cooled (−60° C.; 2-propanone/CO₂bath) mixture of ethanedioyl dichloride (0.1 mol) in CH₂Cl₂ (350 ml) wasadded sulfinylbis[methane] (30 ml) during 10 minutes. After stirring 10minutes, a mixture of interm. 10 in CH₂Cl₂ (90 ml) was added during 5minutes. After stirring for 15 minutes, N,N-diethylethanamine (125 ml)was added. When the mixture was warmed up to room temperature, it waspoured out in water. The product was extracted with CH₂Cl₂. The organiclayer was washed with water, HCl (1 M), water, NaHCO₃ (10%) and water,dried and evaporated. The residue was dissolved in diethyl ether, washedwith water, dried, filtered and evaporated. The residue was purified bycolumn chromotoghaphy over silica gel (eluent: CHCl₃). The desiredfraction was collected and the eluent was evaporated. Yield: 21.6 g of6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (interm. 11)

e) Preparation of

nButyllithium 1.6 M (0.056 mol) was added slowly at −70° C. to asolution of intermediate (5) (0.046 mol) in THF (100 ml). The mixturewas stirred at −70° C. for 30 minutes. A suspension of interm. 11 (0.056mol) in THF (100 ml) was added slowly. The mixture was stirred at −70°C. for 1 hour, then brought to room temperature, poured out into H₂O andextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (21 g) was purifiedby column chromatography over silica gel (eluent: cyclohexane/EtOAc80/10; 15-35 μm). The pure fractions were collected and the solvent wasevaporated. Yield: 9.5 g of interm. 12 (55%).

EXAMPLE A8

a) Preparation of

A mixture of intermediate (5) (0.1127 mol), 2-methoxyethanamine (0.2254mol) and K₂CO₃ (0.2254 mol) in DMF (500 ml) was stirred at 120° C. for15 hours and then cooled. The solvent was evaporated. The residue wastaken up in CH₂Cl₂ and H2O. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated till dryness. Theresidue (33.53 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH 99.5/0.5; 15-40 μm). Two fractions were collectedand their solvents were evaporated. Yield: 5.7 g of interm. 14 (38%) andinterm. 13 (34%).

b) Preparation of

A mixture of intermediate (5) (0.0751 mol), thiomorpholine (0.0891 mol)and K₂CO₃ (0.15 mol) in DMF (200 ml) was stirred at 120° C. for 12hours. The solvent was evaporated till dryness. The residue was taken upin CH₂Cl₂ and H₂O. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (26 g) was purifiedby column chromatography over silica gel (eluent: cyclohexane/EtOAc80/20; 20-45 μm). Two factions were collected and their solvents wereevaporated. The two fractions were combined. Yield: 9.4 g of interm. 15(37%); mp. 82° C.

EXAMPLE A9

a) 4-Aminobenzoic acid (0.219 mol) was added to a solution of sodium3-nitrobenzenesulfonate (0.118 mol) in H₂SO₄ 70% (230 ml) and themixture was stirred and refluxed. 2-propene-1,1-diol, 2-methyl-,diacetate (0.216 mol) was added dropwise and the mixture was refluxedfor 4 hours. Ethanol (200 ml) was added and the mixture was stirred at80° C. for 48 hours. The mixture was evaporated, the residue was pouredinto ice water/NH₄OH and extracted with CH₂Cl₂. The organic layer wasdried (MgSO₄) and evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/2-propanol 99/1). Thepure fractions were collected and evaporated. Yield: 21 g of ethyl3-methyl-6-quinolinecarboxylate (interm. 16) (45%).

b) Interm. 16 (0.098 mol) in THF (270 ml) was added at 0° C. to asolution of LiAlH₄ (0.098 mol) in THF under N₂. When the addition wascomplete, water (10 ml) was added. The precipitate was filtered off andwashed with CH₂Cl₂. The organic layer was dried (MgSO₄), filtered offand evaporated. The product was used without further purification.Yield: 16.71 g of 3-methyl-6-quinolinemethanol (interm. 17).

c) MnO₂ (0.237 mol) was added to a solution of interm. 17 (0.096 mol) inCH₂Cl₂ (200 ml) and the mixture was stirred at room temperature for 12hours. The mixture was filtered through celite and the filtrate wasstirred again with MnO₂ (20 g) for 12 hours. MnO₂ (10 g) was addedagain. The mixture was stirred for 12 hours. The mixture was filteredthrough celite and evaporated. The product was used without furtherpurification. Yield: 11.71 g of 3-methyl-6-quinolinecarboxaldehyde (71%)(interm. 18).

d) A solution of bromocyclohexyl (0.14 mol) in 1,1′-oxybisethane (50 ml)and Mg turnings (50 ml) was added at 10° C. to a mixture of THF (0.14mol) in 1,1′-oxybisethane (10 ml). A solution of interm. 18 (0.07 mol)in Mg turnings (100 ml) was added carefully at 5° C., the mixture waspoured into ice water and extracted with EtOAc. Yield: 11.34 g of(±)-α-cyclohexyl-3-methyl-6-quinolinemethanol (63%) (interm. 19).

EXAMPLE A10

Preparation of

A mixture of compound (5) (0.001507 mol),tributyl(1-ethoxyethenyl)stannane (0.00226 mol) and Pd(PPh₃)₄ (0.000151mol) in 1,4-dioxane (5 ml) was stirred at 80° C. for 3 hours. Water wasadded. The mixture was extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Thisproduct was used without further purification. Yield: 1.4 g of interm.20.

EXAMPLE A11

Preparation of

A mixture of compound (45) (prepared according to B6) (0.00125 mol) inNaOH 3N (5 ml) and iPrOH (1.7 ml) was stirred at room temperatureovernight, then poured out into H₂O, acidified with HCl 3N and extractedwith EtOAc. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated. The residue was taken up in diethyl ether.The precipitate was filtered off and dried. Yielding: 0.26 g ofintermediate 23 (56%). (mp.: 232° C.)

EXAMPLE A12

a. Preparation of

A mixture of 5-bromo-1H-indole-2,3-dione (0.221 mol) in NaOH 3N (500 ml0was stirred at 80° C. for 30 minutes, brought to room temperature and2-pentanone (0.221 mol) was added. The mixture was stir and refluxed for1 hour and 30 minutes and acidified with AcOH until pH=5. Theprecipitate was filtered, washed with water and dried. Yielding 52.3 gof intermediate 24 and intermediate 25. (Total yielding: 80%).

b. Preparation of

nBuLi 1.6 M (0.0816 mol) was added dropwise at −78° C. to a suspensionof intermediate 25 (0.034 mol) and intermediate 26 (0.034 mol) in THF(300 ml) under N₂ flow. The mixture was stirred at −78° C. for 30minutes. nBuLi 1.6 M (0.0816 mol) was added dropwise. The mixture wasstirred for 1 hour. A mixture of intermediate 9 (0.102 mol) in THF (250ml) was added slowly. The mixture was stirred for −78° C. to −20° C.,poured out into H₂O/HCl 3N and extracted with EtOAc. The organic layerwas separated, dried (MgSO₄), filtered, and the solvent was evaporatedtill dryness. Yielding: 20.89 g of compound intermediate 26 andintermediate 27 (86%).

EXAMPLE A13

a. Preparation of

4-amino-3-methoxybenzoic acid (0.054 mol) was added portionwise at roomtemperature to a solution of 3-chloro-2-ethyl-2-butenal (0.065 mol) inAcOH (100 ml). The mixture was stirred and refluxed for 8 hours andevaporated to dryness. The residue was taken up in CH₂Cl₂, water wasadded and the solution was basified by Et₃N. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was crystallized from 2-propanone. The precipitate was filteredoff and dried. Yielding: 2.5 g of interm. 26 (18%).

b. Preparation of

CDI (0.012 mol) was added at room temperature to a solution of interm.26 (0.011 mol) in CH₂Cl₂ (30 ml). The mixture was sired at roomtemperature for 1 hour. methoxyaminomethyl (0.012 mol) was added and themixture was stirred at room temperature for 8 hours. H₂O was added. Aprecipitate was filtered off. The filtrate was extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered, and thesolvent was evaporated. The residue was crystallized from diethyl ether.The precipitate was filtered off and dried. Yielding: 0.95 g of interm.27 (31%) (mp.:148° C.).

EXAMPLE A14

Preparation of

4-Bromobenzenamine (0.034 mol) was added at room temperature to asolution of 3-chloride-2-ethyl-2-butanal (0.041 mol) in AcOH (60 ml).The mixture was stirred and refluxed for 8 hours, brought to roomtemperature and evaporated to dryness. The product was crystallized fromEtOAc. The precipitate was filtered, washed with K2CO3 10% and taken upin CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, andthe solvent was evaporated. Yielding: 4.6 g of interm. 28 (54%).

EXAMPLE A15

a. Preparation of

A solution of KOH (0.326 mol) in H₂O (150 ml) was added slowly at 5° C.to a solution of 1,3-cyclohexanedione (0.268 mol) in H₂O (150 ml). Thetemperature must not reach 12° C. KI (2 g) then2-bromo-1-(4-nitrophenyl)ethanone (0.294 mol) were added portionwise.The mixture was stirred at room temperature for 48 hours. Theprecipitate was filtered, washed with H₂O then with diethyl ether anddried. Yielding: 63 g (85%). A part of this fraction (1 g) wascrystallized from EtOH. The precipitate was filtered off and dried.Yielding: 0.5 g of interm. 29 (42%) (mp.: 100° C.).

b. Preparation of

A mixture of interm. 29 (0.145 mol) in H₂SO₄ (40 ml) was stirred at roomtemperature for 1 hour, poured out into ice, basified with NH₄OH andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue was crystallizedfrom EtOH. The precipitate was filtered off and dried. Yielding: 31 g(58%). A part of this fraction (1 g) was crystallized from EtOH. Theprecipitate was filtered off and dried. Yielding: 0.7 g of interm. 30(58%) (mp.:200° C.).

c. Preparation of

A mixture of interm. 30 (0.039 mol), Raney Ni (10 g) in EtOH (100 ml)was hydrogenated at room temperature under a 3 bar pressure for 1 hour.The mixture was filtered over celite and washed with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered, and the solvent wasevaporated. The residue (9.5 g) was crystallized from diethyl ether. Theprecipitate was filtered off and dried. Yielding: 4.6 g (52%). Thefiltrate was evaporated. The residue (2.7 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH; 99/1; 15-40 μm).Two fractions were collected and the solvent was evaporated. Yielding:1.6 g F1 and 1.2 g F2. F2 was crystallized from EtOH. The precipitatewas filtered off and dried. Yielding: 0.24 g of interm. 31 (2%)(mp.:202° C.).

d. Preparation of

Interm. 30 (0.02 mol) was added at room temperature to a solution of3-chloro-2-ethyl-2-butenal (0.04 mol) in AcOH (50 ml). The mixture wasstirred and refluxed for 4 hours. The solvent was evaporated tilldryness. The residue was crystallized from EtOAc. The precipitate wasfiltered off and dried. The residue was taken up in CH₂Cl₂. The mixturewas basified with K₂CO₃ 10% and extracted with CH₂Cl₂. The organic layerwas separated, dried (MgSO₄), filtered, and the solvent was evaporated.The residue was crystallized from EtOH. The precipitate was filtered offand dried. Yielding: 2.5 g of interm. 32 (40%).

EXAMPLE A16

Preparation of

A mixture of 2-(4-nitrophenyl)-1-phenylethanone (0.083 mol) and Raney Ni(20 g) in EtOH (200 ml) was hydrogenated at room temperature for 1 hourunder a 3 bar pressure, then filtered over celite, washed withCH₂Cl₂/CH₃OH and dried. Yielding: 17.5 g of interm. 33 (97%).

B. Preparation of the Final Compounds

EXAMPLE B1

Preparation of

POCl₃ (0.024 mol) was added slowly at 5° C. to DMF (0.024 mol). Themixture was stirred at room temperature for 30 minutes, then cooled to5° C. 3-Oxo-butanoic acid ethyl ester (0.024 mol) was added slowly. Themixture was stirred at 5° C. for 30 minutes.1-(4-aminophenyl)-2-phenylethanone (0.024 mol) was added portionwise.The mixture was stirred at 90° C. for 3 hours and dissolved in CH₂Cl₂.Ice water was added. The mixture was basified with NH₄OH and extractedwith CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered,and the solvent was evaporated. The residue was crystallized from2-propanone/diethyl ether. The precipitate was filtered off and dried.Yielding: 0.9 g of compound 306 (11%) (mp.:136° C.).

EXAMPLE B2

Preparation of

KMnO₄ (10 g) was added portionwise at room temperature to a solution of

(prepared according to example A7.e) (0.022 mol) intris(dioxa-3,6-heptyl)amine (1 ml) and CH₂Cl₂ (100 ml). The mixture wasstirred at room temperature for 8 hours, filtered over celite, washedwith CH₂Cl₂ and dried. The residue (6 g, 100%) was crystallized fromdiethyl ether/petroleum ether. The precipitate was filtered off anddried. Yield: 2 g of compound (2) (33%); mp. 82° C.

EXAMPLE B3

a) Preparation of

nBuLi 1.6 M (0.07 mol) was added slowly at −70° C. to a solution ofintermediate (5) (0.058 mol) in THF (150 ml). The mixture was stirred at−70° C. for 30 minutes. A solution of2,3-dihydro-1H-Indene-2-carbonitrile (0.07 mol) in THF (100 ml) wasadded slowly. The mixture was stirred at −70° C. for 1 hour, broughtslowly to room temperature, hydrolized with H₂O and extracted withEtOAc. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue (22 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/cyclohexane 80/20 to 100;15-35 μm). The pure fractions were collected and the solvent wasevaporated. The second fraction was crystallized from2-propanone/diethyl ether. The precipitate was filtered off and dried.Yield: 0.11 g of compound (3). The filtrate was concentrated. Yield:0.55 g of compound (3); mp. 145° C.

b) Preparation of

nBuLi 1.6 M (0.022 mol) was added slowly at −70° C. to a solution ofintermediate (5) (0.018 mol) in THF (50 ml). The mixture was stirred at−70° C. for 1 hour, brought to −40° C., then cooled to −70° C. Asolution of interm. 7 (0.018 mol) in THF (40 ml) was added slowly. Themixture was stirred at −70° C. for 1 hour, then brought to −20° C.,hydrolyzed with H₂O and extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (6.5 g) was purified by column chromatography over silica gel(eluent: toluene/EtOAc 90/10; 15-40 μM). Two fractions (F1 and F2) werecollected and the solvent was evaporated. F1 (2.4 g) was crystallizedfrom diethyl ether. The precipitate was filtered off and dried. Yield:1.8 g of compound (4) (29%); mp. 123° C. F2 (0.9 g) was crystallizedfrom diethyl ether. The precipitate was filtered off and dried. Yield:0.2 g of compound (5) (3%); mp. 120° C.

c) Preparation of

nBuLi 1.6 M in exane (0.107 mol) was added dropwise at −78° C. under N₂flow to a mixture of intermediate (6) (0.089 mol) in THF. The mixturewas stirred at −78° C. for 1 hour. A mixture of interm. 7 (150 ml) wasadded at −78° C. under N₂ flow. The mixture was stirred at −78° C. for 2hours, brought to 0° C., poured out into H₂O and extracted with EtOAc.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. The residue (31 g) was purified by column chromatographyover silica gel (eluent: cyclohexane/EtOAc 85/15; 20-45 μm). Two purefractions were collected and their solvents were evaporated. Yielding:11 g of compound (7) (38%) and 8.2 g of compound (8) (28%).

d) Preparation of

A solution of chloromethylbenzeen (0.0069 mol) in diethyl ether (8 ml)was added slowly to a suspension of Mg (0.0069 mol) in a small amount ofdiethyl ether. The mixture was stirred at room temperature for 30minutes (disparition of Mg), then cooled to 5° C. A solution of interm.27 (0.0027 mol) in THF (8 ml) was added slowly. The mixture was stirredat 5° C. for 15 minutes, then at room temperature for 2 hours, pouredout into H₂O and filtered over celite. The precipitate was washed withEtOAc. The filtrate was extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue (1 g) was purified by column chromatography over kromasil(eluent: CH₂Cl₂ 100 to CH₂Cl₂/CH₃OH 99/1; 15-40 μm). The pure fractionswere collected and the solvent was evaporated. The residue (0.5 g, 56%)was crystallized from diethyl ether. The precipitate was filtered offand dried. Yielding: 0.14 g of compound 503 (15%).

EXAMPLE B4 Examples of Endgoup Modifications

a) Preparation of

A mixture of

(prepared according to example B3.c) (0.018 mol) in HCl 3N (60 ml) andTHF (60 ml) was stirred at 60° C. overnight. The mixture was basifiedwith a K₂CO₃ 10% solution and extracted with CH₂C₂. The organic layerwas separated, dried (MgSO₄), filtered and the solvent was evaporated.Yield: 4.6 g of compound (156) (82%).

b) Preparation of

A mixture of

(prepared according to example B3.c) (0.0122 mol) in HCl 3N (40 ml) andTHF (40 ml) was stirred and refluxed overnight, poured out into water,basified with K₂CO₃ 10% and extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:cyclohexane/EtOAc 40/60; 15-40 μm). The pure fractions were collectedand the solvent was evaporated. Yield: 2 g of compound (9) (52%); mp.226° C.

c) Preparation of

A mixture of compound (4) (0.0015 mol), 2-methoxyethanamine (0.003 mol)and K₂CO₃ (0.003 mol) in DMF (5 ml) was stirred at 140° C. for 48 hours.H₂O was added. The mixture was extracted with EtOAc. The organic layerwas separated, dried (MgSO₄), filtered and the solvent was evaporated.The residue (1 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc 60/40; 15-40 μm). Two fractions werecollected and the solvent was evaporated. Both fractions werecrystallized separately from pentane. The precipitate was filtered offand dried. Yield: 0.05 g of compound (10) (9%; mp. 115° C.) and 0.057 gof compound (11) (10%; mp. 107° C.).

d) Preparation of

A mixture of compound (4) (0.0015 mol) in 2-(methylthio)ethanamine (2ml) was stirred at 120° C. for 8 hours. K₂CO₃ 10% was added. The mixturewas extracted with CH₂Cl₂. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue (2.2 g)was purified by column chromatography over silica gel (eluent:cyclohexane/EtOAc 70/30; 15-40 μm). Two fractions were collected and thesolvent was evaporated. The first fraction was crystallized from diethylether/petroleum ether. The precipitate was filtered off and dried.Yield: 0.08 g of compound (12) (14%); mp. 120° C. The second fractionwas crystallized from diethyl ether. The precipitate was filtered offand dried. Yield: 0.18 g of compound (13) (31%); mp. 125° C.

e) Preparation of

A mixture of compound (4) (0.001507 mol), ethynyltrimethylsilane(0.003013 mol), CuI (0.000151 mol) and Pd(PPh₃)₄ (0.000151 mol) inN,N-diethylethanamine (5 ml) was stirred at 100° C. for 24 hours. Waterwas added. The mixture was filtered over celite, washed with EtOAc andthe filtrate was extracted with EtOAc. The organic layer was separated,dried (MgSO₄), filtered and the solvent was evaporated. The residue (1.3g) was purified by column chromatography over silica gel (eluent:cyclohexane/EtOAc 85/15; 15-40 μm). The pure fractions were collectedand the solvent was evaporated. The residue (0.3 g) was crystallizedfrom pentane. The precipitate was filtered off and dried. Yield: 0.11 gof compound (14) (18%); mp. 114° C.

f) Preparation of

A mixture of compound (14) (0.013 mol) and KF (0.038 mol) in acetic acid(50 ml) was stirred at room temperature for 2 hours. H₂O was added andthe mixture was extracted with diethyl ether. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (4.4 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc 70/30; 15-40 μm). One fraction was collectedand the solvent was evaporated. This fraction (3 g, 73%) wascrystallized from diethyl ether. The precipitate was filtered off anddried. Yield: 2.45 g of compound (15) (60%); mp. 132° C.

g) Preparation of

A mixture of

prepared according to example B.7.a) (0.0056 mol) in KOH [1M, H₂O] (10ml) and methanol (30 ml) was stirred at room temperature for 1 hour,poured out into water and extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (2.2 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc 85/15 to 70/30; 15-40 μm). Two fractions werecollected and the solvent was evaporated.

The first fraction was crystallized from diethyl ether. The precipitatewas filtered off and dried. Yield: 0.2 g of compound (15) (11%); mp.133° C.

The second fraction was crystallized from diethyl ether. The precipitatewas filtered off and dried. Yield: 0.3 g of compound (17) (16%); mp.128° C.

h) Preparation of

A mixture of compound (4) (0.001205 mol), 2-propyn-1-ol (0.002411 mol),Pd(PPh₃)₄ (0.000121 mol) and CuI (0.000121 mol) in N,N-diethylethanamine(5 ml) was stirred at 100° C. for 2 hours. Water was added. The mixturewas filtered over celite, washed with EtOAc and extracted aith EtOAc.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. The residue (0.7 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2; 15-40 μm).The pure fractions were collected and the solvent was evaporated. Theresidue was crystallized from petroleum ether and diethyl ether. Theprecipitate was filtered off and dried. Yield. 0.1 g of compound (18)(23%); mp. 113° C.

i) Preparation of

A mixture of compound (4) (0.006027 mol) and KF (0.024108 mol) in DMSO(20 ml) was stirred at 140° C. The solvent was evaporated till dryness.The residue was solidified in water and diethyl ether. The mixture wasextracted with diethyl ether. The organic layer was separated, washedwith diethyl ether, washed with a saturated solution of NaCl, dried(MgSO₄), filtered and the solvent was evaporated. The residue (1.7 g)was purified by column chromatography over silica gel (eluent:cyclohexane/EtOAc 85/15; 15-40 μm). Three fractions were collected andtheir solvents were evaporated.

The first fraction was crystallized from petroleum ether. Theprecipitate was filtered off and dried. Yield: 0.21 g of compound (19)(11%); mp. 92° C.

The second fraction was crystallized from petroleum ether. Theprecipitate was filtered off and dried. Yield: 0.33 g of compound (20)(17%); mp. 114° C.

j) Preparation of

A mixture of compound (4) (0.003013 mol), acetyl chloride (0.003315 mol)and sodium iodide (0.006027 mol) in CH₃CN (10 ml) was stirred andrefluxed for 1 hour. K₂CO₃ 10% was added. The mixture was extracted withCH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue (1 g) was purified by columnchromatography over silica gel (eluent: cyclohexane/EtOAc 80/20; 15-40μm). Two fractions were collected and their solvents were evaporated.The first fraction was crystallized from petroleum ether. Theprecipitate was filtered off and dried. Yield: 0.12 g of compound (21);mp. 110° C.

k) Preparation of

A mixture of compound (21) (0.000898 mol), trimethylsilanecarbonitrile(0.001347 mol) and Pd(PPh₃)₄ (0.00009 mol) in N,N-diethylethanamine (5ml) was stirred at 100° C. for 2 hours. Water was added. The mixture wasextracted with EtOAc. The organic layer was separated, dried (MgSO₄).filtered and the solvent was evaporated. The residue (0.4 g) waspurified by column chromatography over silica gel (eluent:cyclohexane/EtOAc 80/20; 15-40 μm). The pure fractions were collectedand the solvent was evaporated. The residue (0.18 g, 62%) wascrystallized from petroleum ether. The precipitate was filtered off anddried. Yield: 0.13 g of compound (22) (45%); mp. 138° C.

l) Preparation of

A mixture of compound (4) (0.00603 mol), Pd(OAc)₂ (0.000603 mol), PPh₃(0.00904 mol) and K₂CO₃ (0.012054 mol) in CO (gas) and methanol (40 ml)was stirred at 90° C. for 8 hours under a 5 bar pressure of CO. H₂O wasadded. The mixture was extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (6 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/CH₃OH 100/0 to 98/2; 15-35 μm). Four fractions (F1-F4)were collected and the solvent was evaporated. Yield: 0.13 g (cis) F1;0.02 g F2 (cis, compound 25); 0.055 g F3 (trans, 3%) and 0.11 g F4(trans; compound 26).

F1 was crystallized from petroleum ether. The precipitate was filteredoff and dried. Yield: 0.03 g of compound (23) (1%); mp. 91° C.

F3 was crystallized from petroleum ether. The precipitate was filteredoff and dried. Yield: 0.035 g of compound (24) (1%); mp. 99° C.

m) Preparation of

A mixture of compound (4) (0.009 mol) and Zn (0.027 mol) in acetic acid(30 ml) was stirred at 60° C. for 4 hours, filtered over celite, washedwith CH₂Cl₂, evaporated till dryness, solubilized in CH₂Cl₂ and washedwith K₂CO₃ 10%. The organic layer was separated, dried (MgSO₄), filteredand the solvent was evaporated. The residue (4 g) was purified by columnchromatography over silica gel (eluent: cyclohexane/EtOAc 75/25; 15-40μm). One fraction was collected and the solvent was evaporated. Thisfraction (1 g 37%) was crystallized from petroleum ether. Theprecipitate was filtered off and dried. Yield: compound (25); mp. 88° C.

n) Preparation of

A mixture of compound (4) (0.001502 mol), Sn(CH₃)₄ (0.003004 mol) andPd(PPh₃)₄ (0.00015 mol) in methylbenzene (5 ml) was stirred and refluxedfor 3 hours. K₂CO₃ 10% was added. The mixture was extracted with EtOAc.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. The residue (0.7 g) was purified by columnchromatography over silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40μm). Two fractions (F1 and F2) were collected and their solvents wereevaporated. Yield: 0.27 g (F 1, starting material) and 0.14 g (F2). F2was crystallized from pentane and petroleum ether. The precipitate wasfiltered off and dried. Yield: 0.08 g of compound (27) (17%); mp. 110°C.

o) Preparation of

A mixture of compound (4) (0.001507 mol), tributylethenylstannane(0.002260 mol) and Pd(PPh₃)₄ (0.000151 mol) in dioxane (5 ml) wasstirred at 80° C. for 8 hours. Water was added. The mixture was filteredover celite, washed with EtOAc and extracted with EtOAc. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (0.65 g) was purified by column chromatographyover silica gel (eluent: cyclohexane/EtOAc 90/10; 15-40 μm). The purefractions were collected and the solvent was evaporated. The residue wascrystallized from petroleum ether. The precipitate was filtered off anddried. Yield: 0.07 g of compound (28) (14%); mp. 108° C.

p) Preparation of

A mixture of compound (5) (0.001507 mol),triphenyl(phenylmethyl)stannane (0.002260 mol) and Pd(PPh₃)₄ (0.000151mol) in dioxane (5 ml) was stirred at 80° C. for 8 hours. Water wasadded. The mixture was extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (1.4 g) was purified by column chromatography over silica gel(eluent: CH₂Cl₂/EtOAc 96/4; 15-40 μm). The pure fractions were collectedand the solvent was evaporated. The residue (0.38 g) was crystallizedfrom petroleum ether. The precipitate was filtered off and dried. Yield:0.16 g of compound (29) (28%); mp. 112° C.

q) Preparation of

A mixture of compound (4) (0.001507 mol), tributyl-2-thienylstannane(0.00226 mol) and Pd(PPh₃)₄ (0.0001507 mol) in dioxane (5 ml) wasstirred at 80° C. for 8 hours. K₂CO₃ 10% was added. The mixture wasextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue (1.7 g) waspurified by column chromatography over silica gel (eluent:cyclohexane/EtOAc 85/15; 15-40 μm). The pure fractions were collectedand the solvent was evaporated. The residue (0.65 g) was crystallizedfrom diethyl ether. The precipitate was filtered off and dried. Yield:0.35 g of compound (30) (61%); mp. 142° C.

r) Preparation of

A mixture of compound (4) (0.0015 mol), 3-thienyl boronic acid (0.00226mol), Pd(PPh₃)₄ (0.00015 mol) and dioxane was stirred and refluxed for24 hours. K₂CO₃ 10% was added. The mixture was extracted with EtOAc. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (0.8 g) was purified by column chromatographyover silica gel (eluent: cyclohexane/EtOAc is 80/20; 15-40 μm). The purefractions were collected and the solvent was evaporated. The residue(0.4 g, 70%) was crystallized from petroleum ether. The precipitate wasfiltered off and dried. Yield: 0.39 g of compound (31) (68%); mp. 113°C.

s) Preparation of

A mixture of compound (4) (0.003 mol), glycine methyl estermonohydrochloride (0.0066 mol) and Pd(PPh)₄ (0.0003 mol) in Et₃N (2 ml)and toluene (10 ml) was stirred at 100° C. under 5 bar pressure of COfor 8 hours, filtered over celite, washed with CH₂Cl₂ and evaporated.The residue (2 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc 80/20; 75-35 μm). One fraction was collectedand the solvent was evaporated. This fraction (1 g 80%) was crystallizedfrom diethyl ether. The precipitate was filtered off and dried.Yielding: 0.46 g of compound (32) (37%).

t) Preparation of

A mixture of compound (4) (0.003 mol) and hydrazinecarboxaldehyde(0.0045 mol) in 1-butanol (15 ml) was stirred and refluxed overnight,poured out into water and extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1; 15-40 μm). Two fractions (F1 and F2) werecollected and their solvents were evaporated. Yield: 0.3 g F1 and 0.3 gF2.

F1 was crystallized from CH₃CN and diethyl ether. The precipitate wasfiltered off and dried. Yield: 0.102 g of compound (33); mp. 224° C.

F2 was crystallized from CH₃CN and diethyl ether. The precipitate wasfiltered off and dried. Yield: 0.2 g of compound (34); mp. 185° C.

u) Preparation of

A mixture of compound 4 (0.015 mol) and NaN₃ (0.045 mol) in DMF (50 ml)was stirred at 140° C. for 2 hours. K₂CO₃10% was added and the mixturewas extracted with EtOAc. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue (6 g) waspurified by column chromatography over silica gel (eluent:cyclohexane/EtOAc 60/40; 15-40 μm). The first fraction was collected andthe solvent was evaporated. The residue was crystallized from diethylether. The precipitate was filtered off and dried. Yield: 1.26 g ofcompound (35) (24%); mp. 160° C.

v) Preparation of

A mixture of compound (4) (0.009 mol) and thiourea (0.0099 mol) in ethylalcohol (30 ml) was stirred and refluxed for 12 hours and a solution ofKOH (0.0149 mol) in H₂O (5 ml) was added slowly. The mixture was stirredand refluxed for 1 hour, poured out into water and extracted withCH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (cyclohexane/EtOAc 70/30; 15-40 μm). Thepure fractions were collected and the solvent was evaporated. Yielding:1.1 g of F1 (37%) and 0.4 g of F2 (13%). F1 was crystallized from2-propanone. The precipitate was filtered off and dried. Yielding:compound (36). F2 was crystallized from 2-propanone. The precipitate wasfiltered off and dried. Yielding: compound (37).

w) Preparation of

CH₃I (0.0034 mol) was added slowly at room temperature to a solution ofcompound (36) (0.0015 mol), compound (37) (0.0015 mol) and K₂CO₃ (0.0034mol) in acetone (15 ml). The mixture was stirred at room temperature for8 hours. Water was added and the mixture was extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue (1.2 g) was purified by column chromatographyover silica gel (eluent: cyclohexane/EtOAc 85/15; 15-40 μm). The purefractions were collected and the solvent was evaporated. Yielding: 0.6 gF1 (57%), and 0.18 g F2 (17%). F1 was crystallized from diethyl ether.The precipitate was filtered off and dried. Yielding: 0.28 g compound(38) (27%). F2 was crystallized from diethyl ether. The precipitate wasfiltered off and dried. Yielding: 0.065 g of compound (39) (6%).

x) Preparation of

A mixture of

prepared according to example B3b (0.0014 mol) in HCl 3N (5 ml) and THF(5 ml) was stirred and refluxed for a weekend, then poured out into H₂O,basified with K₂CO₃ and extracted with CH₂Cl₂. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated.Yielding: 0.5 g of F. This fraction F was crystallized from 2-propanone.The precipitate was filtered off and dried. Yielding: 0.35 g of compound(40) (74%).

y) Preparation of

A mixture of compound (5) (0.045 mol), acetamide (0.90013 mol) and K₂CO₃(0.225 mol) was stirred and refluxed at 200° C. for 2 hours, cooled atroom temperature, poured out into H₂O/CH₂Cl₂; and extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated till dryness. The residue (14.4 g) was crystallized fromCH₃OH. The precipitate was filtered off and dried. The filtrate wasevaporated. The residue (11.27 g) was purified by column chromatographyover silica gel (eluent CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.1; 15-35 μm). The purefractions were collected and the solvent was evaporated. Yielding: 4.2 gof compound (188) (65%).

z) Preparation of

A mixture of compound (188) (0.00032 mol), benzoic acid (1.5 equiv.,0.00048 mol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide. HCl (1:1)(1.5 equiv., 0.00048 mol), N-hydroxybenzotriazole (1.5 equiv., 0.00048mol) and Et₃N (1 equiv., 0.00032 mol) in CH₂CL₂ (2 ml) was stirred atroom temperature for 15 hours. The solvent was evaporated. The residuewas purified by HPLC and the product fractions were collected and thesolvent was evaporated. Yield: 0.066 g of compound (205) (49.50%).

aa) Preparation of

A mixture of interm. 20 (0.001507 mol) in HCl 3N (10 ml) and THF (10 ml)was stirred at room temperature for 8 hours, basified with K₂CO₃ 10% andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporate. The residue (1.2 g) was purifiedby column chromatography over silica gel (eluent: cyclohexane/EtOAc85/15; 15-40 μm). The pure fractions were collected and the solvent wasevaporated. The residue (0.4 g) was crystallized from petroleum ether.The precipitate was filtered off and dried. Yield: 0.3 g of compound (6)(58%); mp. 108° C.

ab) Preparation of

A mixture of compound 213 (prepared according to B4) (0.00305 mol) andCH₃ONa (30% in CH₃OH) (0.00916 mol) in CH₃OH (25 ml) was stirred andrefluxed for 15 hours then cooled to room temperature, poured out intoH₂O and extracted with EtOAc. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated till dryness. Theresidue (1.1 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc; 40/60; 15-40 μm). Two fractions werecollected and the solvent was evaporated. Yielding: 0.3 g F1 and 0.5 gF2 (50%) F2 was crystallized from diethyl ether/petroleum ether. Theprecipitate was filtered off and dried. Yielding: 0.26 g F1 wascrystallized from pentane. The precipitate was filtered off and dried.Yielding: 0.19 g. This fraction was purified by column chromatographyover silica gel (eluent: CH₂Cl₂/CH₃OH; 98/2; 15-40 μm). The purefractions were collected and the solvent was evaporated. Yielding: 0.11g. This fraction was purified by column chromatography over kromasil(eluent: CH₃OH/H₂O; 70/30). The pure fractions were collected and thesolvent was evaporated. Yielding: 0.09 g. (9%) This fraction wascrystallized from diethyl ether. The precipitate was filtered off anddried. Yielding: 0.08 g of compound 419 (8%).

EXAMPLE B5

Preparation of

Iodomethane (0.00456 mol) was added at 5° C. to a mixture of compound(9) (0.0019 mol), compound (8) (0.0019 mol) and tBuOK (0.00456 mol) inTHF (30 ml) under N₂ flow. The mixture was stirred at room temperatureovernight, poured out into H₂O and extracted with CH₂Cl₂. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: cyclohexane/EtOAc 65/35; 15-40 μm). Two fractionswere collected and the solvent was evaporated. Yield: 0.35 g of compound(42) (30%; mp. 125° C.) and 0.35 g of compound (43) (30%; mp. 116° C.).

EXAMPLE B6

a) Preparation of

NaH 60% (0.01068 mol) was added at 0° C. under N₂ flow to a mixture ofcompound (8) and compound (9) (0.0089 mol). The mixture was stirred for30 minutes.

Ethyl bromoacetate (0.01068 mol) was added at 0° C. The mixture wasstirred at room temperature for 1 hour, hydrolized with water andextracted with EtOAc. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: cyclohexane/EtOAc 60/40;15-40 μm). The desired fractions (F1-F4) were collected and the solventwas evaporated. Yield: 0.11 g F1; 0.13 g F2; 0.75 g F3 and 0.8 g F4.

F3 was crystallized from diethyl ether. The precipitate was filtered offand dried. Yield: compound (44); mp. 152° C.

F4 was crystallized from diethyl ether. The precipitate was filtered offand dried. Yield: compound (45); mp. 147° C.

b) Preparation of

Bromomethylbenzene (0.007 mol) was added dropwise at 0° C. under N₂ flowto a solution of compound (8) and compound (9) (0.0064 mol) and NaH 60%(0.007 mol) in DMF (40 ml). The mixture was stirred at room temperaturefor 1 hour, hydrolized with water and extracted with EtOAc. The organiclayer was separated, washed with water, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: cyclohexane/EtOAc 70/30; 15-40μm). The desired fractions (F1-F4) were collected and the solvent wasevaporated. Yield: 0.15 g F1, 0.1 g F2, 0.6 g F3 (23%) and 0.8 g F4.

F3 was crystallized from diethyl ether. The precipitate was filtered offand dried. Yield: 0.13 g of compound (46); mp. 137° C.

F4 was crystallized from DIPE and petroleum ether. The precipitate wasfiltered off and dried. Yield: compound (47); mp. 130° C.

EXAMPLE B7

a) 3-Chlorobenzenecarboperoxoic acid (0.088 mol) was added at 0° C. to asolution of compound (48) (prepared according to example B2) (0.044 mol)in CH₂Cl₂ (200 ml) and the mixture was stirred at room temperature for12 hours. The mixture was washed with K₂CO₃10%. The organic layer wasdried (MgSO₄), filtered off and evaporated. The residue wasrecrystallized from (C₂H₅)₂O. Yield: 8.2 g ofcyclohexyl(3-methyl-6-quinolinyl)methanone,1-oxide (compound 49) (69%).

b) 4-Methyl benzenesulfonyl chloride (0.043 mol) was added to a solutionof compound (49) (0.028 mol) in K₂CO₃ (400 m) and CH₂Cl₂ (400 ml) andthe mixture was stirred at room temperature for 1 hour. The mixture wasextracted with CH₂Cl₂. The organic layer was dried (MgSO₄), filtered offand evaporated. The residue was recrystallized from (C₂H₅)₂O. Yield:6.64 g of 6-(cyclohexylcarbonyl)-3-methyl-2(1H)-quinolinone (compound50) (85%); mp. 256.1° C.

EXAMPLE B8

a) Preparation of

A mixture of compound (7) (0.0229 mol), hydroxylamine (0.0252 mol) andN,N-diethylethanamine (0.0252 mol) in ethanol (100 ml) was stirred andrefluxed for 6 hours, poured out into water and extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. The residue was crystallized from CH₃CN. The precipitatewas filtered off and dried. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/EtOAc 80/20; 15-40 μm).Two fractions were collected and the solvent was evaporated. Yielding:2.8 g of compound (44) (36%; mp. 133° C.) and 3 g of compound (45) (38%;mp. 142° C.).

b) Preparation of

Hydrazine (0.41 mol) was added at room temperature to a solution ofcompound (7) (0.015 mol) in ethanol (75 ml). The mixture was stirred andrefluxed for 1 night, poured out into water and extracted with CH₂Cl₂.The organic layer was separated, dried (MgSO₄), filtered and the solventwas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1). The pure fractionswere collected and the solvent was evaporated. The residue wascrystallized from diethyl ether. The precipitate was filtered off anddried. Yielding: 0.8 g of compound (53) (15%); mp. 110° C.

EXAMPLE B9

Preparation of

Procedure for compounds 400, 401, 402, 403, 404 and 405. A mixture ofinterm. 21 (prepared according to A11) (0.000269 mol), amantadinehydrochloride (0.000404 mol; 1.5 eq.),N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine hydrochloride(0.000404 mol; 1.5 equiv.), 1-hydroxy-1H-benzotriazole (0.000404 mol;1.5 equiv.) and Et₃N (0.000269 mol) in CH₂Cl₃ (2 ml) was stirred at roomtemperature for 12 hours. The solvent was evaporated. The residue waspurified by HPLC. The product fractions were collected and the solventwas evaporated. Yield: 0.063 g of compound 520 (46.37%).

EXAMPLE B10

Preparation of

A mixture of intermediate 27 (0.0026 mol) and intermediate 26 (0.0026mol) in EtOH (380 ml) and H₂SO₄ conc. (19 ml) was stirred and refluxedfor 15 hours, the cooled to room temperature, poured out into ice water,basified with K₂CO₃ and extracted with EtOAc. The organic layer wasseparated, dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue (17.9 g) was purified by column chromatography over silica gel(eluent: cyclohexane/EtOAc; 80/20; 15-35 μm). The pure fractions werecollected and the solvent was evaporated. Yielding: 0.85 g of F1, 1.1 gF2 and 11.5 g of F3. F1 and F2 were crystallized separately frompetroleum ether. The precipitate was filtered off and dried. Yielding:0.34 g of compound 233.

EXAMPLE B11

Preparation of

A mixture of compound 22 (prepared according to B4) (0.004 mol) in HCl(3N) (20 ml) and THF (20 ml) was stirred and refluxed for 8 hours,poured out on ice, basified with NH₄OH and extracted with CH₂Cl₂. Theorganic layer was separated, dried (MgSO₄), filtered, and the solventwas evaporated. The residue (1.2 g) was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH; 93/7/0.5;15-40 μm). Two fractions were collected and the solvent was evaporated.Yielding: 0.5 g F1 (41%) and 0.4 g of F2. F1 was crystallized frompetroleum ether. The precipitate was filtered off and dried. Yielding:0.17 g of compound 511 (14%).

EXAMPLE B12

Preparation of

A mixture of compound 524 (prepared according to B9a) (0.0018 mol) andKOH 85% (0.0094 mol) in EtOH (15 ml) was stirred and refluxed for 24hours, poured out into H₂O and extracted with CH₂Cl₂. The organic layerwas separated, dried (MgSO4), filtered, and the solvent was evaporated.The residue was purified by column chromatography over silica gel(eluent: CH₂Cl₂/Cyclohexane 80/20; 15-40 μm). Two fractions werecollected and the solvent was evaporated. Yielding: 0.35 g F1 (64%) and0.17 g (SM) F1 was crystallized from diethyl ether. The precipitate wasfiltered off and dried. Yielding: 0.33 g of compound 514 (60%) (mp.:185°C.).

EXAMPLE B13

Preparation of

A mixture of interm. 28 (0.019 mol), 2-benzofuranylboronic acid (0.028mol), Pd(PPh₃)₄ (0.001 mol) and BHT (a few quantity) in dioxane (25 ml)and Na₂CO₃ [2] (25 ml) was stirred and refluxed for 8 hours andextracted with EtOAc. The aqueous layer was basified with NH₄OH andextracted with CH₂Cl₂. The organic layer was separated, dried (MgSO₄),filtered, and the solvent was evaporated. The residue (3.6 g) waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH99/1; 15-40 μm). The pure fractions were collected and the solvent wasevaporated. Yielding: 1.8 g (33%). This fraction was crystallized from2-propanone/diethyl ether. The precipitate was filtered off and dried.Yielding: 0.39 g of compound 515 (7%) (mp.:134° C.).

EXAMPLE B14

Preparation of

Triethylsilane (0.0012 mol) was added slowly at room temperature to asolution of interm. 32 (0.004 mol) in CF₃COOH (5 ml) and AcOH (10 ml).NaBH₄ (0.0012 mol) was added portionwise under N₂ flow. The mixture wasstirred at room temperature for 8 hours, poured out on ice, basifiedwith K₂CO₃ and extracted with CH₂Cl₂. The organic layer was separated,dried (MgSO₄), filtered, and the solvent was evaporated. The residue(1.2 g) was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 99/1; 15-40 μm). Two fractions were collected and thesolvent was evaporated. Yielding: 0.5 g F1 (43%) and 0.4 g F2. F1 wasdissolved in iPrOH. HCl/iPrOH (1 eq) were added. The precipitate wasfiltered off and dried; Yielding: 0.32 g of compound 526 (mp.: 248° C.).

EXAMPLE B15

Preparation of

A mixture of interm. 33 (0.082 mol) and 3-chloro-2-ethyl-2-butenal(0.098 mol) in AcOH (200 ml) was stirred and refluxed for 8 hours. Thesolvent was evaporated till dryness. The residue was dissolved in CH₂Cl₂and washed with K₂CO₃ 10%. The organic layer was separated, dried(MgSO₄), filtered, and the solvent was evaporated. The residue (27 g)was purified by column chromatography over silica gel (eluent:CH₂Cl₂/EtOAc 95/5 to 92/8; 15-35 μm). Two fractions were collected andthe solvent was evaporated. Yielding: 0.7 g of F1 and 5.3 g F2. F1 wascrystallized from 2-propanone/diethyl ether. The precipitate wasfiltered off and dried. Yielding: 0.25 g of compound 471 (2%) (mp.: 140°C.).

Tables 1 to 8 list the compounds of formula (I-A) and (I-B) which wereprepared according to one of the above examples.

TABLE 1

Co. Ex. physical no. no. R² R³ R⁴ R¹ data 54 B2 Cl ethyl H

— 3 B3a Cl ethyl H

mp. 145° C. 55 B3b Cl ethyl H

mp. 131° C. 56 B3b Cl ethyl H

mp. 104° C. 57 B3b Cl ethyl H phenylethyl mp. 100° C. 58 B3b Cl ethyl H

mp. 126° C. 59 B3b Cl ethyl H

mp. 150° C. 60 B3b Cl ethyl H

mp. 138° C. 61 B3b OCH₃ ethyl H

— 62 B3b OCH₃ ethyl H

mp. 130° C. 63 B3b OCH₃ ethyl H

mp. 116° C. 64 B3b Cl ethyl H —(CH₂)₂—O—CH₃ mp. 82° C. 65 B3b OCH₃ ethylH 1-methylcyclohexyl mp. 82° C. 66 B3b OCH₃ ethyl H 3-methoxycyclohexyltrans; mp. 94° C. 67 B3b OCH₃ ethyl H 3-methoxycyclohexyl cis; mp. 108°C. 68 B3b OCH₃ ethyl H 4-(methylethoxy- (A), cyclohexyl mp. 820° C. 69B3b OCH₃ ethyl H 4-[C(CH₃)₃]cyclohexyl cis; mp. 92° C. 70 B3b OCH₃ ethylH 4-[C(CH₃)₃]cyclohexyl trans; mp. 108° C. 71 B3b OCH₃ ethyl H4-methylcyclohexyl (B), mp. 92° C. 72 B3b OCH₃ ethyl H4-methylcyclohexyl (A), mp. 80° C. 2 B2 Cl ethyl H CH₂—CH(CH₃)₂ mp. 82°C. 73 B3b Cl ethyl H —CH₂—O—C₂H₅ mp. 82° C. 48 B2 H methyl H cyclohexl —74 B4 I ethyl H

— 75 B4 I ethyl H

mp. 124° C. 76 B4 I ethyl H

mp. 138° C. 77 B4 I ethyl H

mp. 120° C. 78 B4 CN ethyl H

mp. 128° C. 79 B4 CN ethyl H

mp. 136° C. 80 B4 CN ethyl H

mp. 120° C. 81 B4 CN ethyl H

mp. 139° C. 82 B4 methyl ethyl H

mp. 106° C. 83 B4 methyl ethyl H

mp. 149° C. 84 B4 methyl ethyl H

mp. 118° C. 85 B4 methyl ethyl H

mp. 180° C. 86 B4 methyl ethyl H phenylethyl mp. 53° C. 87 B4 methylethyl H

mp. 87° C. 88 B4 methyl ethyl H —CH₂—CH(CH₃)₂ mp. 68° C. 89 B4 methylethyl H

mp. 120° C. 31 B4 3-thiazolyl ethyl H 4-methoxycyclohexyl cis; 113° C.90 B3b OCH₃ H H 4-methoxycyclohexyl trans, mp. 126° C. 91 B3b OCH₃ H H4-methoxycyclohexyl cis, mp. 100° C. 92 B3b OCH₃ H CH₃4-methoxycyclohexyl cis; mp. 120° C. 93 B3b OCH₃ H CH₃4-methoxycyclohexyl trans; mp. 111° C. 94 B3b OCH₃ methyl H4-methoxycyclohexyl cis, mp. 96° C. 95 B3b OCH₃ phenyl H4-methoxycyclohexyl cis; HCl (1:1), mp. 138° C. 96 B3b OCH₃ propyl H4-methoxycyclohexyl trans; mp. 118° C. 97 B3b OCH₃ propyl H4-methoxycyclohexyl cis; mp. 108° C. 98 B3b OCH₃ methyl H4-methoxycyclohexyl cis; mp. 104° C. 99 B4 N(CH₃)₂ ethyl H

(B); mp. 102° C. 100 B3b Cl ethyl H

mp. 114° C. 101 B4 methyl ethyl H 4-butoxycyclohexyl cis; mp. 86° C. 102B3b Cl ethyl H

mp. 78° C. 103 B3b Cl ethyl H

mp. 91° C. 104 B4 N(CH₃)₂ ethyl H

mp. 103° C. 105 B4 N(CH₃)₂ ethyl H

mp. 170° C. 106 B3b Cl ethyl H

mp. 137° C. 107 B3b Cl ethyl H

mp. 137° C. 108 B4 methyl ethyl ethyl 4-methoxycyclohexyl cis; mp. 91°C. 109 B4 methyl ethyl H 4-ethoxycyclohexyl trans; mp. 150° C. 110 B4methyl ethyl H

mp. 90° C. 111 B4 methyl ethyl H

mp. 94° C. 112 B4 methyl ethyl H

mp. 176° C. 113 B4 methyl ethyl H

mp. 106° C. 114 B4 propyl H H 4-methoxycyclohexyl cis; mp. 74° C. 115 B4methyl ethyl H 4-ethoxycyclohexyl cis; mp. 108° C. 116 B4 methyl ethyl H

mp. 110° C. 117 B3b Cl ethyl H

mp. 124° C. 118 B3b Cl ethyl H

mp. 107° C. 119 B3b Cl ethyl H

mp. 129° C. 120 B4 methyl ethyl H

mp. 106° C. 41 B3b Cl ethyl H

trans; mp. 157° C. 182 B3b methyl ethyl H

cis; mp. 170° C. 183 B3b methyl ethyl H

trans; mp. 144° C. 184 B3b methyl ethyl H

mp. 138° C. 185 B3b Cl ethyl H

mp. 120° C. 186 B3b Cl ethyl H

187 B3b methyl ethyl H

mp. 162° C. 216 B4 C≡N ethyl H

mp.: 160° C. 217 B4 methyl ethyl H

.ethanedioate (1:1); mp.: 143° C. 218 B4 I ethyl H

mp.: 102° C. 219 B4 C≡N ethyl H

mp.: 115° C. 220 B4 Cl ethyl H

(A); mp.: 107° C. 221 B4 Cl ethyl H

(B); mp.: 113° C. 222 B4 I ethyl H

mp.: 206° C. 223 B4 Cl ethyl H

(trans); mp.;117° C. 224 B4 methyl ethyl H

(A); mp. 103° C. 225 B2 Cl ethyl H

mp.: 94° C. 226 B3b Cl ethyl H

(trans); mp.: 157° C. 227 B3c methoxy

H

mp.: 204° C. 228 B4 Cl ethyl H

(A); mp.: 136° C. 229 B3b n-propyl H H

(trans);.HCl (1:1); mp.:150° C. 230 B3b Cl ethyl H

mp.: 116° C. 231 B3b Cl ethyl H

mp.: 120° C. 232 B3b Cl ethyl H

mp.: 112° C. 233 B10 i-propyl H C(═O)O—C₂H₅

(cis); mp.: 91° C. 234 B4 methyl ethyl H

mp.: 122° C. 235 B4 methyl ethyl H

mp.: 106° C. 236 B4 methyl ethyl H

mp.: 104° C. 237 B4 methyl ethyl H

mp.: 90° C. 238 B4 methyl H H

(cis); mp.: 80° C. 239 B3b Cl ethyl H

(trans); mp.: 126° C. 240 B3b Cl ethyl H

(cis); mp.: 128° C. 241 B4 methyl ethyl H

(A); mp.: 90° C. 242 B4 methyl ethyl H

(B); mp.: 110° C. 243 B3b Cl ethyl H

mp.: 134° C. 244 B3b Cl ethyl H

mp.: 127° C. 245 B4 NHC(═O)NH₂ ethyl H

(cis); mp.: 176° C. 246 B4 methyl ethyl H

(B) 247 B3b Cl ethyl H

mp.: 92° C. 248 B4 methyl ethyl H

(A); mp.: 80° C. 249 B3b Cl ethyl H

(B); mp.: 138° C. 250 B4 methyl ethyl H

(trans); mp.: 118° C. 251 B4 methyl ethyl H

(B);.HCl (1:1) 252 B3b Cl ethyl H

(A) 253 B3b Cl ethyl H

(B) 254 B3b methyl ethyl H

mp.: 74° C. 255 B4 methyl ethyl H

(cis); mp.: 68° C. 256 B4 methyl ethyl H

mp.: 210° C. 257 B4 methyl ethyl H

mp.. 113° C. 258 B4 methyl ethyl H

mp.: 92° C. 259 B3b methyl ethyl H

mp.: 115° C. 260 B3b methyl ethyl H

mp.: 60° C. 261 B3b Cl ethyl H

(A); mp.: 86° C. 262 B3b Cl ethyl H

(B); mp.: 101° C. 263 B3b methyl ethyl H

mp.: 130° C. 264 B3b Cl ethyl H

(A); mp.: 124° C. 265 B3b Cl ethyl H

(B); mp.: 126° C. 266 B4 N(CH₃)₂ ethyl H

(trans), mp.: 102° C. 267 B4 N(CH₃)₂ ethyl H

(cis);.HCl (1:1); mp.: 170° C. 268 B4 methyl ethyl H

(A);.HCl (1:1); mp.: 206° C. 269 B4 methyl ethyl H

mp.: 104° C. 270 B3b methyl ethyl H

mp.: 117° C. 271 B4 NCH₂H₅OCH₃ ethyl H

— 272 B4 methyl ethyl H

— 273 B4 NH₂ ethyl H

— 274 B3b Cl ethyl H

— 275 B3b Cl ethyl H

mp.: 99° C. 276 B3b Cl ethyl H

mp.: 95° C. 277 B4 methyl ethyl H

mp.: 105° C. 278 B3b Cl ethyl H

mp.: 141° C. 279 B4 Cl ethyl H

mp.: 168° C. 280 B4 Cl ethyl H

— 281 B4 Cl ethyl H

mp.: 140° C. 282 B4 Cl ethyl H

mp.: 169° C. 283 B4 methyl ethyl H

mp.: 96° C. 284 B3b Cl CH₂N(CH₃)₂ H

mp.: 115° C. 285 B4 methyl ethyl H

mp.: 133° C. 286 B4 methyl CH₂OCH₃ H

(trans); mp.: 106° C. 287 B4 methyl CH₂N(CH₃)₂ H

(cis); mp.: 110° C. 288 B3b Cl n-propyl H

mp.: 110° C. 289 B4 NH₂ ethyl H

mp.: 218° C. 290 B4 methyl n-propyl H

mp.: 90° C. 291 B3b Cl n-propyl H

(cis); mp.: 128° C. 292 B3b Cl n-propyl H

(trans); mp.: 104° C. 293 B3b Cl ethyl H

mp.:106° C. 294 B4 methyl n-propyl H

(cis); mp.: 94° C. 295 B4 methyl CH₂N(CH₃)₂ H

mp.: 83° C. 296 B3b Cl ethyl H

mp.: 99° C. 297 B3b Cl ethyl H

mp.: 110° C. 298 B4 methyl ethyl H

mp.: 93° C. 299 B4 methyl ethyl H

mp.: 105° C. 300 B4 methyl ethyl H

mp.: 114° C. 301 B3b methyl ethyl H

mp.: 143° C. 302 B4 methoxy ethyl H

mp.: 93° C. 303 B4 methyl ethyl H

mp.: 82° C. 304 B4 n-butyl ethyl H

— 305 B3b Cl n-propyl H

mp.: 125° C. 306 B1 methyl C(═O)OC₂H₅ H

mp.: 136° C. 307 B4 methyl n-propyl H

mp.: 81° C. 308 B4 methoxy n-propyl H

mp.: 80° C. 309 B4 I n-propyl H

mp.: 120° C. 310 B3d methyl ethyl H

.HCl(1:1); mp.: 129° C. 311 B3b Cl H H

mp.: 160° C. 312 B3b Cl H H

(trans); mp.: 145° C. 313 B3b Cl H H

mp.: 103° C. 314 B4 n-propyl n-propyl H

.HCl (1:1); mp.: 150° C. 315 B4 n-propyl ethyl H

.HCl (1:1) 316 B4 n-propyl H H

.HCl (1:1); mp.: 140° C. 317 B3b Cl H H

mp.: 168° C. 318 B4 methyl n-propyl H

.HCl (1:1); mp.: 200° C. 509 B3b Cl ethyl H

— 510 B4 methyl ethyl H

.H₂O (1:1) 513 B4 methyl ethyl H

— 516 B4 Cl ethyl H

mp.: 120° C. 517 B4 I ethyl H CH₂CH(CH₃)₂ — 518 B4 Cl ethyl H

— 519 B4 Cl ethyl H

(A + B) 521 B4 I ethyl H

— 522 B4 methyl ethyl H

(A) 1 B4 methyl ethyl H

(A) 525 B4 Cl ethyl H

527 B4 F ethyl H

mp.: 116° C.

TABLE 2

Co. Ex. no. no. R² X physical data 5 B3b Cl O trans; mp. 120° C. 121 B3b1-piperidinyl O cis; HCl (1:1) 122 B3b 1-piperidinyl O trans; HCl (1:1);mp. 128° C. 123 B3b 4-thiomorpholinyl O cis; mp. 105° C. 124 B3b4-thiomorpholinyl O trans; mp. 115° C. 125 B3b 4-morpholinyl O trans;mp. 118° C. 126 B3b 4-morpholinyl O cis; mp. 118° C. 127 B3b —N(CH₃)₂ Otrans; mp. 96° C. 128 B3b —N(CH₃)₂ O cis; mp. 114° C. 4 B3b Cl O cis;mp. 123° C. 8 B3c OCH₃ O trans, mp. 68° C. 7 B3c OCH₃ O cis, mp. 116° C.6 B4 acetyl O trans; mp. 108° C. 129 B4 acetyl O cis; mp. 106° C. 11 B4NH—(CH₂)₂—OCH₃ O trans; mp. 107° C. 10 B4 NH—(CH₂)₂—OCH₃ O cis; mp. 115°C. 12 B4 NH—(CH₂)₂—SCH₃ O cis; mp. 120° C. 13 B4 NH—(CH₂)₂—SCH₃ O trans;mp. 125° C. 14 B4 —C≡C—Si(CH₃)₃ O cis; mp. 114° C. 16 B4 —C≡C—Si(CH₃)₃ Otrans; mp. 108° C. 15 B4 —C≡CH O cis; mp. 132-133° C. 17 B4 —C≡CH Otrans; mp. 128° C. 18 B4 —C≡C—CH2OH O cis; mp. 113° C. 130 B4 —C≡C—CH₂OHO trans; mp. 108° C. 19 B4 F O cis; mp. 92-99° C. 20 B4 F O trans; mp.114° C. 21 B4 I O cis; mp. 110° C. 22 B4 CN O cis; mp. 137-138° C. 26 B4H O trans 23 B4 —C(═O)—OCH₃ O cis; mp. 91° C. 24 B4 —C(═O)—OCH₃ O trans;mp. 99° C. 25 B4 H O cis; mp. 88° C. 27 B4 methyl O cis; mp. 110-112° C.131 B4 methyl O trans; mp. 25° C. 28 B4 ethenyl O cis; mp. 108° C. 132B4 ethenyl O trans; mp. 103° C. 29 B4 phenyl O trans; mp. 112° C. 30 B42-thienyl O cis; 142° C. 133 B4 2-thiazolyl O cis; 108° C. 134 B42-furanyl O cis; mp. 105° C. 51 B8a OCH₃ N—OH [1α(A), 4α]; mp. 133° C.52 B8a OCH₃ N—OH [1α(B), 4α]; mp. 142° C. 53 B8b OCH₃ NNH₂ [1α(Z), 4α];mp. 110° C. 135 B4 NH₂ O cis; mp. 203° C. 136 B4 NH₂ O trans; mp. 202°C. 137 B4 —C(═O)—OCH(CH₃)₂ O cis; mp. 105° C. 138 B4 —C(═O)—OCH(CH₃)₂ Otrans; mp. 88° C. 38 B4 SCH₃ O cis; mp. 124° C. 39 B4 SCH₃ O trans; mp.116° C. 32 B4

O cis; mp. 130° C. 139 B4 ethyl O cis; mp.180° C. 188 B4 NH₂ O cis +trans 189 B4

O cis; mp. 154° C. 190 B4

O trans; mp. 156° C. 191 B4

O cis; mp. >260° C. 192 B4

O .H₂O (1:1); trans; mp. 248° C. 193 B4

O cis; mp. 224° C. 194 B4

O trans; mp. 234° C. 195 B4

O cis; mp. 108° C. 196 B4

O trans; mp. 127° C. 197 B4

O cis; mp. 150° C. 198 B4

O trans; mp. 90° C. 199 B4

O LC/MS [M + H]⁺; 475.4 200 B4

O LC/MS [M + H]⁺; 464.3 201 B4

O LC/MS [M + H]⁺; 523.3 202 B4

O LC/MS [M + H]⁺; 465.3 203 B4

O LC/MS [M + H]⁺; 475.4 204 B4

O LC/MS [M + H]⁺; 465.3 205 B4

O — 319 B4

O (cis); .ethanedioate (1:1); mp.: 160° C. 320 B4

O (cis); mp.: 150° C. 321 B4 methoxy CH₂ (cis); .HCl (1:1); mp.:118° C.322 B4 n-butyl O (cis); .HCl (1:1); mp.:158° C. 323 B4

O — 324 B4

O — 325 B4

O — 326 B4

O — 327 B4

O — 328 B4

O — 329 B4

O — 330 B4

O — 331 B4

O — 332 B4

O — 333 B4

O — 334 B4

O — 335 B4

O — 336 B4

O — 337 B4

O — 338 B4

O — 339 B4

O — 340 B4

O — 341 B4

O — 342 B4

O — 343 B4

O — 344 B4

O — 345 B4

O — 346 B4

O — 347 B4

O — 348 B4 CH₂OC(═O)CH₃ O (cis); mp.: 74° C. 349 B4

O — 350 B4

O — 351 B4

O — 352 B4

O — 353 B4

O (A); .HCl (1:2) .H2O (1:1); mp.: 166° C. 354 B4

O (cis) 355 B4

O — 356 B4

O — 357 B4

O — 358 B4

O — 359 B4

O — 360 B4

O — 361 B4

O — 362 B4

O — 363 B4

O — 364 B4

O — 365 B4

O — 366 B4

O — 367 B4

O — 368 B4

O — 369 B4

O — 370 B4

O — 371 B4

O — 372 B4

O — 373 B4

O — 374 B4

O — 375 B4

O — 376 B4

O — 377 B4

O — 378 B4

O — 379 B4

O — 380 B4

O — 381 B4

O — 382 B4

O — 383 B4

O (cia); mp.: 148° C. 384 B4

O (trans); mp.: 141° C. 385 B4

O mp.: 130° C. 386 B4

O (cia); mp.: 140° C. 387 B4

O (trans); mp.: 155° C.

TABLE 3

Co. Ex. no. no. Y. R¹ physical data 140 B4 O

mp. 220° C. 141 B4 O

mp. 213° C. 142 B4 O

mp. 148° C. 143 B4 O 1-methylcyclohexyl mp. 195-210° C. 144 B4 O3-methoxycyclohexyl cis; mp. 156° C. 145 B4 O 3-methoxycyclohexyl trans;mp. 156-163° C. 146 B4 O 4-(dimethylethyl)cyclohexyl mp. 230° C. 147 B4O 4-(methylethoxy)cyclohexyl mp. 186° C. 148 B4 O 4-methylcyclohexytrans; mp. 214° C. 36 B4 S 4-methoxycyclohexyl cis; mp. 224° C. 37 B4 S4-methoxycyclohexyl trans; mp. 220° C. 149 B4 O

mp. 188° C. 40 B4 O

mp. 192° C. 150 B4 O

cis; mp. 226° C. 151 B4 O

trans; mp. 226° C. 152 B4 O

mp. 213° C. 153 B4 O

mp. 200° C. 154 B4 O

mp. 210° C. 155 B4 O 4,4-dimethylcyclohexyl mp. 242° C. 388 B4 OCH₂CH(CH₃)₂ mp. 189° C. 389 B4 O

mp. 228° C. 390 B4 O

mp. 197° C. 391 B4 O

mp. 145° C. 392 B4 O

mp. 192° C. 393 B4 O

(B); mp.: 224° C. 394 B4 O

(A); mp.: 201° C. 395 B4 O

(A); mp.: 207° C. 396 B4 O

mp.: 212° C. 397 B4 O

(B); mp.: 238° C. 398 B4 O

mp.: 234° C. 399 B4 O

(cis); mp.:192° C.

TABLE 4

Co. Ex. no. no. R³ R⁴ R⁵ R physical data 156 B4 ethyl H H OCH₃ trans;mp. 252° C. 157 B4 H H H OCH₃ (cis + trans); mp. 244° C. 158 B4 H methylH OCH₃ cis; mp. >260° C. 159 B4 methyl H H OCH₃ cis; mp. 254° C. 160 B4methyl H H OCH₃ trans; mp.>260° C. 161 B4 propyl H H OCH₃ mp. 208° C.162 B4 propyl H H OCH₃ trans; mp. 232° C. 9 B4 ethyl H H OCH₃ cis; mp.224-226° C. 43 B5 ethyl H CH₃ OCH₃ trans; mp. 116° C. 42 B5 ethyl H CH₃OCH₃ cis; mp. 125° C. 44 B6 ethyl H CH₂—COOC₂H5 OCH₃ cis; mp. 152° C. 45B4 ethyl H CH₂—COOC₂H5 OCH₃ trans; mp. 147° C. 46 B4 ethyl H benzyl OCH₃cis; mp.137° C. 47 B4 ethyl H benzyl OCH₃ trans; mp. 130° C. 50 B7methyl H H H mp. 256.1° C. 163 B4 ethyl ethyl H OCH₃ cis; mp. 221° C.164 B4 ethyl ethyl H OCH₃ cis; mp. 221° C. 165 B4 ethyl ethyl H OCH₃trans; mp.215° C. 166 B4 ethyl H

OCH₃ LC/MS [M + H]⁺; 429.4 167 B4 ethyl H

OCH₃ LC/MS [M + H]⁺; 451.3 168 B4 H H H OCH₃ cis; mp. 106° C. 169 B4ethyl H

OCH₃ LC/MS [M + H]⁺; 409.3 400 B9 ethyl H

OCH₃ — 401 B9 ethyl H

OCH₃ — 402 B9 ethyl H

OCH₃ — 403 B9 ethyl H

OCH₃ — 404 B9 ethyl H

OCH₃ — 405 B9 ethyl H

OCH₃ — 406 B4 ethyl H

OCH₃ — 407 B4 ethyl H

OCH₃ — 408 B4 ethyl H

OCH₃ — 409 B3b

H H OCH₃ mp.: 168° C. 410 B4 CH₂OCH₃ H H OCH₃ mp.: 194° C. 508 B4 ethylH

OCH₃ — 520 B9 ethyl H

OCH₃ —

TABLE 5

Co. Ex. no. no. R⁴ R¹ X physical data 33 B4 H methoxycyclohexyl CH cis;mp. 224° C. 34 B4 H metboxycyclohexyl CH trans; mp. 185° C. 35 B4 Hmethoxycyclohexyl N cis; mp. 160–172° C. 170 B4 H methoxycyclohexyl Ntrans; mp. 146° C. 171 B4 H

N (B); mp. 165° C. 172 B4 H methylcyclohexyl N cis + trans; mp. 143° C.173 B4 ethyl methoxycyclohexyl N cis; mp.: 126° C. 411 B4 H

N mp.: 109° C. 412 B4 H

N mp.: 180° C. 413 B4 H

N (A) 414 B4 H

N mp.: 156° C.

TABLE 6

Co. Ex. no. no. R L physcial data 49 B7 H

— 174 B3b OCH₃

cis; mp. 115° C. 175 B3b OCH₃

trans; mp. 141° C. 176 B3b OCH₃

cis; mp. 149° C. 177 B3b OCH₃

mp. 126° C. 178 B3b OCH₃

trans; mp. 160° C. 179 B3b OCH₃

cis; mp. 119° C. 180 B3b OCH₃

trans; mp. 124° C. 181 B3b OCH₃

trans; mp. 92° C. 206 B3b OCH₃

cis; m.p. 144° C. 207 B3b OCH₃

trans; m.p. 125° C. 208 B3b OCH₃

cis; m.p. 127° C. 209 B3b OCH₃

cis; m.p. 101° C. 210 B3b OCH₃

cis; m.p. 104° C. 211 B3b OCH₃

trans; m.p. 134° C. 212 B4 OCH₃

cis; m.p. 141° C. 213 B4 OCH₃

trans; m.p. 215° C. 214 B4 OCH₃

cis; m.p. 139° C. 215 B3b OCH₃

trans 415 B3b OCH₃

(cis); mp.: 136° C. 416 B3b OCH₃

(cis) 417 B4 OCH₃

(cis); mp.: 149° C. 418 B3b OCH₃

(trans); mp.: 132° C. 419 B4 OCH₃

(cis); mp.: 217° C. 420 B3b OCH₃

(cis); .HCl(1:1); mp.: 200° C. 421 B4 OH

(cis); mp.: 215° C. 422 B4 OH

(trans); mp.: 178° C. 423 B3b OCH₃

mp.: 160° C. 424 B3b OCH₃

(cis); mp.: 106° C. 425 B3b OCH₃

(trans); mp.: 120° C. 426 B3b OCH₃

(cis); mp.: 121° C. 427 B3b H

mp.: 156° C. 428 B3b OCH₃

(cis); mp.: 156° C. 429 B3b OCH₃

(trans); mp.: 197° C. 430 B3b CH₃

(B) 431 B3b CH₃

(A)

TABLE 7

Co. Ex. no. no. R¹ L physcial data 432 B4

mp.: 128° C. 433 B4

mp.: 175° C. 434 B4

mp.: 170° C. 435 B4

mp.: 103° C. 436 B4

mp.: 151° C. 437 B4

(trans); mp.: 110° C. 438 B4

mp.: 150° C. 439 B4

mp.: 150° C. 440 B4

(cis) 441 B4

mp.: 166° C. 442 B4

mp.: 173° C. 443 B4

mp.: 208° C. 444 B4

mp.: 149° C. 445 B4

mp.: 133° C. 446 B3b

mp.: 150° C. 447 B3b

mp.: 165° C. 448 B3b

mp.: 147° C. 449 B3b

mp.: 154° C. 450 B3b

mp.: 157° C. 451 B4

mp.: 190° C. 452 B4

mp.: 187° C. 453 B3b

mp.: 200° C. 454 B3b

mp.: 160° C. 455 B3b

mp.: 139° C. 456 B3b

(A); mp.: 174° C. 457 B3b

(B); mp.: 160° C. 458 B3b

mp.: 184° C. 459 B4

— 460 B4

mp.: 134° C. 461 B4

(B); mp.: 156° C. 462 B4

mp.: 153° C. 463 B3b

mp.: 161° C. 464 B4

mp.: 135° C. 465 B4

mp.: 131° C. 466 B3b

.HCl(1:1); mp.: 206° C. 467 B3d

mp.: 142° C. 468 B4

.hydrate(1:1); mp.: 104° C. 469 B3b dimethylethyl

mp.: 104° C. 470 B3b

mp.: 161° C. 472 B3b

mp.: 144° C. 473 B4

mp.: 143° C. 474 B4

mp.: 196° C. 475 B4

mp.: 162° C. 476 B4

mp.: 171° C. 477 B4

mp.: 155° C. 478 B2 trimethylmethyl

mp.: 124° C. 479 B4

(A); mp.: 146° C. 480 B4

(B); mp.: 162° C. 481 B4

(A); mp.: 129° C. 482 B4

mp.: 115° C. 483 B2

mp.: 187° C. 484 B2

mp.: 162° C. 485 B4

(A); mp.: 130° C. 486 B4

(A); mp.: 124° C. 487 B4

(B); mp.: 128° C. 488 B4

mp.: 85° C. 489 B2

mp.: 150° C. 490 B4

(A); mp.: 117° C. 491 B2

mp.: 220° C. 492 B4

mp.: 136° C. 493 B2

mp.: 131° C. 494 B4

(A); mp.: 125° C. 495 B4

mp.: 135° C. 496 B4

mp.: 139° C. 497 B4

mp.: 127° C. 498 B4

mp.: 195° C. 499 B2

mp.: 201° C. 500 B3b

mp.: 143° C. 501 B3b

mp.: 137° C. 502 B2

mp.: 210° C. 503 B3d

mp.: 134° C. 504 B2

mp.: 163° C. 505 B4

mp.: 142° C. 506 B2

mp.: 139° C. 507 B4

mp.: 171° C. 512 B3b

— 523 B3b

—

TABLE 8 Co. Ex. no. no. Structure physical data 511 B11

— 514 B12

— 515 B13

— 524 B9a

mp.: 185° C. 471 B15

(E) 526 B14

.HCl(1:1)C. Pharmacological ExampleSignal Transduction at the Cloned Rat mGluR1 Receptor in CHO Cells

CHO cells expressing the mGluR1 receptor were plated in precoated black96-well plates. The next day, the effect of the present compounds onglutamate-activated intracellular Ca²⁺ increase was evaluated in afluorescent based assay. The cells were loaded with Fluo-3 AM, plateswere incubated for 1 hour at room temperature in the dark, cells werewashed and the present compounds were added onto the cells for 20minutes. After this incubation time, the glutamate-induced Ca²⁺ rise wasrecorded for each well in function of time using the Fluorescent ImagePlated Reader (FLIPR, Molecular Devices Inc.). Relative fluorescenceunits were recorded and average data graphs of quadruple wells wereobtained. Concentration-response curves were constructed based on peakfluorescence (maximum signal between 1 and 90 seconds) for eachconcentration of tested compound. pIC₅₀ values are the —log values ofthe concentration of tested compounds resulting in 50% inhibition of theglutamated-induced intracellular Ca²⁺ rise.

The compounds according to the present invention exhibited a pIC₅₀ valueof at least 5.

The compounds that are included in the Tables 1-8 exhibited a pIC₅₀value of at least 6.

A particular group of compounds exhibited a pIC₅₀ value between 7 and 8.It concerns the compounds listed in Table 9.

TABLE 9 Com. nr. pIC₅₀ 463 7.98 441 7.95 334 7.95 22 7.94 421 7.94 157.93 440 7.93 139 7.93 178 7.92 338 7.91 87 7.90 462 7.90 394 7.90 4237.89 21 7.87 220 7.87 479 7.86 483 7.86 485 7.84 9 7.84 110 7.84 2487.84 341 7.83 163 7.81 433 7.79 238 7.79 224 7.78 437 7.78 498 7.78 4497.77 242 7.76 346 7.74 182 7.73 486 7.73 447 7.72 7 7.72 175 7.71 4757.71 480 7.71 213 7.70 239 7.70 241 7.67 461 7.65 115 7.64 445 7.63 2817.63 487 7.63 299 7.63 431 7.61 98 7.57 464 7.57 446 7.56 251 7.55 4847.54 494 7.53 128 7.52 344 7.52 161 7.49 298 7.48 454 7.45 456 7.45 2777.44 91 7.43 356 7.42 229 7.41 333 7.41 326 7.41 369 7.40 430 7.39 4357.38 35 7.36 228 7.36 429 7.36 117 7.35 291 7.35 313 7.35 280 7.34 4607.34 482 7.34 343 7.33 425 7.32 473 7.32 287 7.31 448 7.31 243 7.29 3237.28 159 7.28 289 7.27 184 7.26 436 7.26 89 7.25 108 7.25 373 7.25 2557.23 527 7.23 303 7.22 296 7.22 221 7.21 193 7.21 14 7.20 131 7.19 4387.19 148 7.18 496 7.18 236 7.17 332 7.17 481 7.16 191 7.16 457 7.14 207.14 145 7.13 268 7.13 512 7.13 474 7.13 10 7.11 307 7.11 426 7.11 4667.10 97 7.08 83 7.08 434 7.08 300 7.08 199 7.07 290 7.06 112 7.05 3487.05 286 7.03 442 7.03 422 7.02 283 7.02 318 7.02 36 7.00 396 7.00

A particular group of compounds exhibited a pIC₅₀ value of at least 8.It concern the compounds listed in Table 10.

TABLE 10 Comp. nr. Structure pIC50 416

8.587 27

8.527 174

8.49 506

8.48 25

8.45 4

8.4 19

8.38 429

8.38 424

8.355 176

8.33 210

8.315 114

8.28 488

8.27 504

8.27 477

8.25 432

8.237 214

8.233 465

8.145 135

8.14 420

8.135 292

8.13 427

8.115 208

8.095 419

8.065 455

8.055 418

8.045 497

8.025 439

8.023 237

8.01 499

8Cold Allodynia Test in Rats with a Bennett Ligation

Surgery:

Male SD rats, weighing 240-280 g at the time of surgery were used.

For surgery, the animals were anaesthetised with Thalamonal (1 ml;subcutane) and sodium pentobarbital (40 mg/kg; intraperitoneal (IP)).The common sciatic nerve of the left hindpaw was exposed at the level ofthe middle of the thigh by blunt dissection through the biceps femoris.Proximal to the sciatic's trifurcation, about 7 mm of nerve was freedand four loose ligatures with 4.0 chromic gut were placed around thesciatic nerve. Great care was taken to tie the ligatures such that thediameter of the nerve was barely constricted. After surgery, the animalsreceived 1.25 mg/kg naloxone IP.

Cold Plate Testing:

Cold plate testing was performed on a metal plate of 30×30 cm withtransparent acrylic walls around it. The cold plate was cooled to 0.0(±0.5)° C. using a Julabo F25 cooler. For testing, the animal was placedon the cold plate and the duration of lifting of both the left and theright hindpaw was measured during 5 minutes. The difference in liftingtime between the ligated and non-ligated paw was calculated.

Testing Procedure:

At least one week after the operation, animals were placed on the coldplate test and a pre-drug measurement was taken. Animals having adifference in lifting time >25 secondes between the ligated and thenon-ligated paw were selected for drug testing. These selected animalswere injected IP with a compound of the present invention and wereretested after 60 minutes (post drug test). The results obtained duringthe post drug test were expressed as a percentage of those of thepredrug test.

The data were analysed in terms of all or none criterion (based on theresults of control animals) with the limits being:

-   Inhibition: (post-drug/pre-drug)*100<40%-   Antagonism: (post-drug/pre-drug)*100<25%

Compound (27) showed antagonism at a dose of 2.5 mg/kg bodyweight.

1. A compound of formula

an N-oxide form, a pharmaceutically acceptable addition salt, aquaternary amine or a stereochemically isomeric form thereof, wherein Xrepresents O; C(R⁶)₂ with R⁶ being hydrogen, aryl or C₁₋₆alkyloptionally substituted with amino or mono- or di(C₁₋₆alkyl)amino; S orN—R⁷ with R⁷ being amino or hydroxy; R¹ represents C₁₋₆alkyl; thienyl;quinolinyl; cycloC₃₋₁₂alkyl or cycloC₃₋₁₂alkylC₁₋₆alkyl, wherein thecycloC₃₋₁₂alkyl moiety optionally may contain a double bond and whereinone carbon atom in the cycloC₃₋₁₂alkyl moiety may be replaced by anoxygen atom or an NR⁸-moiety with R⁸ being hydrogen, benzyl orC₁₋₆alkyloxycarbonyl; wherein one or more hydrogen atoms in aC₁₋₆alkyl-moiety or in a cycloC₃₋₁₂alkyl-moiety optionally may bereplaced by C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, aminoC₁₋₆alkyl,hydroxy, C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, aryl,amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino,piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical offormula —O—, —O—CH₂—O or —O—CH₂—CH₂—O—; or a radical of formula (a-1)

wherein Z₁ is a single covalent bond, O, NH or CH₂; Z₂ is a singlecovalent bond, O, NH or CH₂; n is an integer of 0, 1, 2 or 3; andwherein each hydrogen atom in the phenyl ring independently mayoptionally be replaced by halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy orhydroxyC₁₋₆alkyl; or X and R¹ may be taken together with the carbon atomto which X and R¹ are attached to form a radical of formula (b-1), (b-2)or (b-3);

R³ represents hydrogen; halo; hydroxy; cyano; C₁₋₆alkyl; C₁₋₆alkyloxy;C₁₋₆alkyloxyC₁₋₆alkyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;C₂₋₆alkenyl; hydroxyC₂₋₆alkenyl; C₂₋₆alkynyl; hydroxyC₂₋₆alkynyl;tri(C₁₋₆alkyl)silaneC₂₋₆alkynyl; amino; mono- or di(C₁₋₆alkyl)amino;mono- or di(C₁₋₆alkyloxyC₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkylthioC₁₋₆alkyl)amino; aryl; morpholinylC₁₋₆alkyl orpiperidinylC₁₋₆alkyl; R⁴ represents hydrogen; halo; hydroxy; cyano;C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxyC₁₋₆alkyl; C₁₋₆alkylcarbonyl;C₁₋₆alkyloxycarbonyl; C₂₋₆alkenyl; hydroxyC₂₋₆alkenyl; C₂₋₆alkynyl;hydroxyC₂₋₆alkynyl; tri(C₁₋₆alkyl)silaneC₂₋₆alkynyl; amino; mono- ordi(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyloxyC₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkylthioC₁₋₆alkyl)amino; morpholinylC₁₋₆alkyl orpiperidinylC₁₋₆alkyl; or R³ and R⁴ may be taken together to form abivalent radical of formula —CH═CH—CH═CH— or —CH₂—CH₂—CH₂—CH₂—; R⁵represents hydrogen; cycloC₃₋₁₂alkyl; piperidinyl; oxo-thienyl;tetrahydrothienyl, arylC₁₋₆alkyl; C₁₋₆alkyloxyC₁₋₆alkyl;C₁₋₆alkyloxycarbonylC₁₋₆alkyl or C₁₋₆alkyl optionally substituted with aradical C(═O)NR_(x)R_(y) in which R_(x) and R_(y), each independentlyare hydrogen, cycloC₃₋₁₂alkyl, C₂₋₆alkynyl or C₁₋₆alkyl optionallysubstituted with cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, furanyl,pyrrolidinyl, benzylthio, pyridinyl, pyrrolyl or thienyl; Y represents Oor S; or Y and R⁵ may be taken together to form ═Y—R⁵— which representsa radical of formula—CH═N—N═  (c-1);—N═N—N═  (c-2); or—N—CH═CH—  (c-3); aryl represents phenyl or naphthyl optionallysubstituted with one or more substituents selected from halo, hydroxy,C₁₋₆alkyl, C₁₋₆alkyloxy, phenyloxy, nitro, amino, thio, C₁₋₆alkylthio,haloC₁₋₆alkyl, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- ordi(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, cyano,—CO—R¹², —CO—OR¹³, —NR¹³SO₂R¹², —SO₂—NR¹³R¹⁴, —NR¹³C(O)R¹²,—C(O)NR¹³R¹⁴, —SOR¹², —SO₂R¹²; wherein each R¹², R¹³ and R¹⁴independently represent C₁₋₆alkyl; cycloC₃₋₆alkyl; phenyl; phenylsubstituted with halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, haloC₁₋₆alkyl,polyhaloC₁₋₆alkyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl oroxazolyl; and when the R¹—C(═X) moiety is linked to another positionthan the 7 or 8 position, then said 7 and 8 position may be substitutedwith R¹⁵ and R¹⁶ wherein either one or both of R¹⁵ and R¹⁶ representsC₁₋₆alkyl, C₁₋₆alkyloxy or R¹⁵ and R¹⁶ taken together may form abivalent radical of formula —CH═CH—CH═CH.
 2. A compound according toclaim 1, wherein X represents O; C(R⁶)₂ with R⁶ being hydrogen or aryl;or N—R⁷ with R⁷ being amino or hydroxy; R¹ represents C₁₋₆alkyl,thienyl; quinolinyl; cycloC₃₋₁₂alkyl or (cycloC₃₋₁₂alkyl)C₁₋₆alkyl,wherein the cycloC₃₋₁₂alkyl moiety optionally may contain a double bondand wherein one carbon atom in the cycloC₃₋₁₂alkyl moiety may bereplaced by an oxygen atom or an NR⁸-moiety with R⁸ being benzyl orC₁₋₆alkyloxycarbonyl; wherein one or more hydrogen atoms in aC₁₋₆alkyl-moiety or in a cycloC₃₋₁₂alkyl-moiety optionally may bereplaced by C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy,arylC₁₋₆alkyloxy, aryl, mono- or di(C₁₋₆alkyl)amino,C₁₋₆alkyloxycarbonylamino, piperazinyl, pyridinyl, morpholinyl, thienylor a bivalent radical of formula —O— or —O—CH₂—CH₂—O—; or a radical offormula (a-1)

wherein Z₁ is a single covalent bond, O or CH₂; Z₂ is a single covalentbond, O or CH₂; n is an integer of 0, 1, or 2; and wherein each hydrogenatom in the phenyl ring independently may optionally be replaced by haloor hydroxy; or X and R¹ may be taken together with the carbon atom towhich X and R¹ are attached to form a radical of formula (b-1), (b-2) or(b-3);

R³ and R⁴ each independently represent hydrogen; C₁₋₆alkyl;C₁₋₆alkyloxyC₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; or R³ and R⁴ may be takentogether to form a bivalent radical of formula —CH═CH—CH═CH— or—CH₂—CH₂—CH₂—CH₂—; R⁵ represents hydrogen; piperidinyl; oxo-thienyl;tetrahydrothienyl, arylC₁₋₆alkyl; C₁₋₆alkyloxycarbonylC₁₋₆alkyl orC₁₋₆alkyl optionally substituted with a radical C(═O)NR_(x)R_(y), inwhich R_(x) and R_(y), each independently are hydrogen, cycloC₃₋₁₂alkyl,C₂₋₆alkynyl or C₁₋₆alkyl optionally substituted with cyano, C₁₋₆alkyloxyor C₁₋₆alkyloxycarbonyl; Y represents O or S; or Y and R⁵ may be takentogether to form ═Y—R⁵— which represents a radical of formula—CH═N—N═  (c-1); or—N═N—N═  (c-2); aryl represents phenyl or naphthyl optionallysubstituted with one or more substituents selected from halo,C₁₋₆alkyloxy, phenyloxy, mono-or di(C₁₋₆alkyl)amino and cyano; and whenthe R¹—C(═X) moiety is linked to another position than the 7 or 8position, then said 7 and 8 position may be substituted with R¹⁵ and R¹⁶wherein either one or both of R¹⁵ and R¹⁶ represents C₁₋₆alkyl or R¹⁵and R¹⁶ taken together may form a bivalent radical of formula—CH═CH—CH═CH—.
 3. A compound according to claim 1, wherein X representsO; R¹ represents C₁₋₆alkyl; cycloC₃₋₁₂alkyl or(cycloC₃₋₁₂alkyl)C₁₋₆alkyl, wherein one or more hydrogen atoms in aC₁₋₆alkyl-moiety or in a cycloC₃₋₁₂alkyl-moiety optionally may bereplaced by C₁₋₆alkyloxy, aryl, or thienyl; R³ and R⁴ each independentlyrepresent hydrogen or C₁₋₆alkyl; or R³ and R⁴ may be taken together toform a bivalent radical of formula —CH₂—CH₂—CH₂—CH₂—; R⁵ representshydrogen; Y represents O; and aryl represents phenyl optionallysubstituted with halo.
 4. A compound as claimed in claim 1, having theformula:


5. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier, and as active ingredient a therapeutically effective amount ofa compound as defined in claim
 1. 6. A process of preparing acomposition as claimed in claim 5, comprising combining apharmaceutically acceptable carrier with a therapeutically effectiveamount of said compound.
 7. A process of preparing a compound of formula(I-B) as claimed in claim 1, comprising a) oxidizing an intermediate offormula (II) in the presence of a suitable oxidizing agent

with Q representing the quinolinone or quinoline-2-thione moiety of acompound of formula (I-B); or b) reacting an intermediate of formula(III) with an intermediate of formula (IV)

with Q representing the quinolinone or quinoline-2-thione moiety of acompound of formula (I-B) and W₁ being a suitable leaving group; or c)reacting an intermediate of formula (V) with an intermediate of formula(IV)

with Q representing the quinolinone or quinoline-2-thione moiety of acompound of formula (I-B) and W₁ being a suitable leaving group; or d)reacting an intermediate of formula (VI) with an intermediate of formula(VII) in the presence of a suitable acid

with R^(1a) being defined as R¹ provided that R¹ is linked to thecarbonyl moiety via a oxygen atom and Q representing the quinolinone orquinoline-2-thione moiety of a compound of formula (I-B); or e) reactingan intermediate of formula (VIII) in the presence of a suitable acid

and, optionally, interconverting a first compound of formula (I-B) toyield a second compound of formula (I-B); and further, optionally,converting the compounds of formula (I-B) into a therapeutically activenon-toxic acid addition salt by treatment with an acid, or convertingthe acid addition salt form into the free base by treatment with alkali;and, optionally, preparing stereachemically isomeric forms, quaternaryamines or N-oxide forms thereof.
 8. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, and as activeingredient a therapeutically effective amount of a compound of formula

an N-oxide form, a pharmaceutically acceptable addition salt, aquaternary amine or a stereochemically isomeric form thereof, wherein Xrepresents O; C(R⁶)₂ with R⁶ being hydrogen, aryl or C₁₋₆alkyloptionally substituted with amino or mono- or di(C₁₋₆alkyl)amino; S orN—R⁷ with R⁷ being amino or hydroxy; R¹ represents C₁₋₆alkyl; thienyl;quinolinyl; cycloC₃₋₁₂alkyl or (cycloC₃₋₁₂alkyl)C₁₋₆alkyl, wherein thecycloC₃₋₁₂alkyl moiety optionally may contain a double bond and whereinone carbon atom in the cycloC₃₋₁₂alkyl moiety may be replaced by anoxygen atom or an NR⁸-moiety with R⁸ being hydrogen, benzyl orC₁₋₆alkyloxycarbonyl; wherein one or more hydrogen atoms in aC₁₋₆alkyl-moiety or in a cycloC₃₋₁₂alkyl-moiety optionally may bereplaced by C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, aminoC₁₋₆alkyl,hydroxy, C₁₋₆alkyloxy, arylC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, aryl,amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino,piperazinyl, pyridinyl, morpholinyl, thienyl or a bivalent radical offormula —O—, —O—CH₂—O or —O—CH₂—CH₂—O—; or a radical of formula (a-1)

wherein Z₁ is a single covalent bond, O, NH or CH₂; Z₂ is a singlecovalent bond, O, NH or CH₂; n is an integer of 0, 1, 2 or 3; andwherein each hydrogen atom in the phenyl ring independently mayoptionally be replaced by halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy orhydroxyC₁₋₆alkyl; or X and R¹ may be taken together with the carbon atomto which X and R¹ are attached to form a radical of formula (b-1), (b-2)or (b-3);

R² represents hydrogen; halo; cyano; C₁₋₆alkyl; C₁₋₆alkyloxy;C₁₋₆alkylthio; C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl;C₁₋₆alkylcarbonyloxyC₁₋₆alkyl; C₂₋₆alkenyl; hydroxyC₂₋₆alkenyl;C₂₋₆alkynyl; hydroxyC₂₋₆alkynyl; tri(C₁₋₆alkyl)silaneC₂₋₆alkynyl; amino;mono- or di(C₁₋₆alkyl)amino; mono- or di(C₁₋₆alkyloxyC₁₋₆alkyl)amino;mono- or di(C₁₋₆alkylthioC₁₋₆alkyl)amino; aryl; arylC₁₋₆alkyl;arylC₂₋₆alkynyl; C₁₋₆alkyloxyC₁₋₆alkylaminoC₁₋₆alkyl; aminocarbonyloptionally substituted with C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,C₁₋₆alkyloxycarbonylC₁₋₆alkyl or pyridinylC₁₋₆alkyl; a heterocycleselected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl,imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl,pyridazinyl, pyrimidinyl, piperidinyl and piperazinyl, optionallyN-substituted with C₁₋₆alkyloxyC₁₋₆alkyl, morpholinyl, thiomorpholinyl,dioxanyl or dithianyl; a radical —NH—C(═O)R⁹ wherein R⁹ representsC₁₋₆alkyl optionally substituted with cycloC₃₋₁₂alkyl, C₁₋₆alkyloxy,C₁₋₆alkyloxycarbonyl, aryl, aryloxy, thienyl, pyridinyl, mono- ordi(C₁₋₆alkyl)amino, C₁₋₆alkylthio, benzylthio, pyridinylthio orpyrimidinylthio; cycloC₃₋₁₂alkyl; cyclohexenyl; amino;arylcycloC₃₋₁₂alkylamino; mono-or-di(C₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkyloxycarbonylC₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkyloxycarbonyl)amino; mono-or di(C₂₋₆alkenyl)amino; mono- ordi(arylC₁₋₆alkyl)amino; mono- or diarylamino; arylC₂₋₆alkenyl;furanylC₂₋₆alkenyl; piperididinyl; piperazinyl; indolyl; furyl;benzofuryl; tetrahydrofuryl; indenyl; adamantyl; pyridinyl; pyrazinyl;aryl; arylC₁₋₆alkylthio or a radical of formula (a-1); a sulfonamid—NH—SO₂—R¹⁰ wherein R¹⁰ represents C₁₋₆alkyl, mono- orpolyhaloC₁₋₆alkyl, arylC₁₋₆alkyl, arylC₂₋₆alkenyl, aryl, quinolinyl,isoxazolyl or di(C₁₋₆alkyl)amino; R³ represents hydrogen; halo; hydroxy;cyano; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxyC₁₋₆alkyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; C₂₋₆alkenyl;hydroxyC₂₋₆alkenyl; C₂₋₆alkynyl; hydroxyC₂₋₆alkynyl;tri(C₁₋₆alkyl)silaneC₂₋₆alkynyl; amino; mono- or di(C₁₋₆alkyl)amino;mono- or di(C₁₋₆alkyloxyC₁₋₆alkyl)amino; mono- ordi(C₁₋₆alkylthioC₁₋₆alkyl)amino; aryl; morpholinylC₁₋₆alkyl orpiperidinylC₁₋₆alkyl; R⁴ represents C₁₋₆alkyloxy or amino; or R² and R³may be taken together to form —R²—R³—, which represents a bivalentradical of formula —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—,—CH═CH—CH═CH—, -Z₄-CH═CH—, —CH═CH-Z₄-, -Z₄-CH₂—CH₂—CH₂—,—CH₂-Z₄-CH₂—CH₂—, —CH₂—CH₂-Z₄-CH₂—, —CH₂—CH₂—CH₂-Z₄-, -Z₄-CH₂—CH₂—,—CH₂-Z₄-CH₂— or —CH₂—CH₂-Z₄-, with Z₄ being O, S, SO₂ or NR¹¹ whereinR¹¹ is hydrogen, C₁₋₆alkyl, benzyl or C₁₋₆alkyloxycarbonyl; and whereineach bivalent radical is optionally substituted with C₁₋₆alkyl; or R³and R⁴ may be taken together to form a bivalent radical of formula—CH═CH—CH═CH— or —CH₂—CH₂—CH₂—CH₂—; aryl represents phenyl or naphthyloptionally substituted with one or more substituents selected from halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, phenyloxy, nitro, amino, thio,C₁₋₆alkylthio, haloC₁₋₆alkyl, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,hydroxyC₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono-ordi(C₁₋₆alkyl)amino; mono-or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, cyano, —CO—R¹²,—CO—OR¹³, —NR¹³SO₂R¹², —SO₂—NR¹³R¹⁴, —NR¹³C(O)R¹², —C(O)NR¹³R¹⁴, —SOR¹²,—SO₂R¹²; wherein each R¹², R¹³ and R¹⁴ independently representC₁₋₆alkyl; cycloC₃₋₆alkyl; phenyl; phenyl substituted with halo,hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, haloC₁₋₆alkyl, polyhaloC₁₋₆alkyl,furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl or oxazolyl; and whenthe R¹—C(═X) moiety is linked to another position than the 7 or 8position, then said 7 and 8 position may be substituted with R¹⁵ and R¹⁶wherein either one or both of R¹⁵ and R¹⁶ represents C₁₋₆alkyl,C₁₋₆alkyloxy or R¹⁵ and R¹⁶ taken together may form a bivalent radicalof formula —CH═CH—CH═CH—.
 9. A process of preparing a composition asclaimed in claim 8, comprising combining a pharmaceutically acceptablecarrier with a therapeutically effective amount of said compound.